Immunotherapeutic agents

ABSTRACT

Cyano and carboxy derivatives of substituted styrenes are inhibitors of tumor necrosis factor α, nuclear factor κB, and phosphodiesterase and can be used to combat cachexia, endotoxic shock, retrovirus replication, asthma, and inflammatory conditions. A typical embodiment is 3,3-bis-(3,4-dimethoxyphenyl)acrylonitrile.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of Ser. No. 10/243,927 filed Sep. 13, 2002, whichis a divisional of Ser. No. 09/906,155 filed Jul. 16, 2001, which is adivisional of Ser. No. 09/639,757 filed Aug. 16, 2000, now U.S. Pat. No.6,262,101, which is a divisional of Ser. No. 08/909,201 filed Aug. 11,1997, now U.S. Pat. No. 5,929,117, which is a continuation-in-part ofSer. No. 08/695,599 filed Aug. 12, 1996, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a method of reducing the level of cytokinesand their precursors in mammals and to compounds and compositions usefultherein. In particular, the invention pertains to a class of compoundswhich mediate the action of phosphodiesterases, particularly PDE III andPDE IV, and the formation of TNFα and NFκB.

Tumor necrosis factor alpha, (TNFα) is a cytokine which is releasedprimarily by mono-nuclear phagocytes in response to immunostimulators.When administered to animals or humans, TNFα can cause inflammation,fever, cardiovascular effects, hemorrhage, coagulation, and acute phaseresponses similar to those seen during acute infections and shockstates.

The nuclear factor κB (NFκB) is a pleiotropic transcriptional activator(Lenardo, et al., Cell 1989, 58, 227–29) which has been implicated in avariety of disease and inflammatory states. NFκB is thought to regulatecytokine levels including, but not limited to, TNFα and to be anactivator of HIV transcription (Dbaibo et al., J. Biol. Chem. 1993,17762–66; Duh et al., Proc. Natl. Acad. Sci. 1989, 86, 5974–78;Bachelerie et al., Nature 1991, 350, 709–12; Boswas et al., J. AcquiredImmune Deficiency Syndrome 1993, 6, 778–786; Suzuki et al., Biochem. AndBiophys. Res. Comm. 1993, 193, 277–83; Suzuki et al., Biochem. AndBiophys. Res Comm. 1992, 189, 1709–15; Suzuki et al., Biochem. Mol. Bio.Int. 1993, 31(4), 693–700; Shakhov et al. 1990, 171, 35–47; and Staal etal., Proc. Natl. Acad. Sci. USA 1990, 87, 9943–47). Thus, inhibition ofNFκB binding can regulate transcription of cytokine gene(s) and throughthis modulation and other mechanisms be useful in the inhibition of amultitude of disease-states. TNFα and NFκB levels are influenced by areciprocal feedback loop.

Many cellular functions are mediated by levels of adenosine 3′,5′-cyclicmonophosphate (cAMP). Such cellular functions can contribute toinflammatory conditions and diseases including asthma, inflammation, andother conditions (Lowe and Cheng, Drugs of the Future, 17(9), 799–807,1992). It has been shown that the elevation of cAMP in inflammatoryleukocytes inhibits their activation and the subsequent release ofinflammatory mediators, including TNFα and NFκB. Increased levels ofcAMP also leads to the relaxation of airway smooth muscle. The primarycellular mechanism for the inactivation of cAMP is the break-down ofcAMP by a family of isoenzymes referred to as cyclic nucleotidephosphodiesterases (PDE), of which seven are known. It is recognized,for example, that the inhibition of PDE type IV is particularlyeffective in both the inhibition of inflammatory mediator release andthe relaxation of airway smooth muscle. Thus, compounds which inhibitPDE IV exhibit the desirable inhibition of inflammation and relaxationof airway smooth muscle with a minimum of unwanted side effects, such ascardio-vascular or anti-platelet effects. It is now known thatinhibition of TNFα production is a consequence of inhibition of PDE IV.L. J. Lombardo, Current Pharinaceutical design, 1, 255–268 (1995).

Excessive or unregulated TNFα production has been implicated in a numberof disease conditions. These include endotoxemia and/or toxic shocksyndrome {Tracey et al. Nature 330, 662–664 (1987) and Hinshaw et al.,Circ. Shock 30, 279–292 (1990)}; cachexia {Dezube et al., Lancet, 335(8690), 662 (1990)}; and Adult Respiratory Distress Syndrome (ARDS)where TNFα concentrations in excess of 12,000 pg/milliliters have beendetected in pulmonary aspirates from ARDS patients {Millar et al.,Lancet 2 (8665), 712–714 (1989)}. Systemic infusion of recombinant TNFαalso resulted in changes typically seen in ARDS {Ferrai-Bialiviera etal., Arch. Surg. 124(12), 1400–1405 (1989)}.

TNFα also appears to be involved in bone resorption diseases, includingarthritis where it has been determined that when activated, leukocyteswill produce a bone-resorbing activity, and data suggests that TNFαcontributes to this activity {Bertolini et al., Nature 319, 516–518(1986) and Johnson et al., Endocrinology 124(3), 1424–1427 (1989)}. Ithas been determined that TNFα stimulates bone resorption and inhibitsbone formation in vitro and in vivo through stimulation of osteoblastformation and activation in combination with inhibition of osteoblastfunction. Although TNFα may be involved in many bone resorptiondiseases, including arthritis, the most compelling link with disease isthe association between production of TNFα by tumor or host tissues andmalignancy associated hypercalcemia {Calci. Tissue Int. (US) 46(Suppl.), S3–10 (1990)}. In Graft versus Host Reaction, increased serumTNFα levels have been associated with major complications followingacute allogenic bone marrow transplants {Holler et al., Blood, 75(4),1011–1016 (1990)}.

Cerebral malaria is a lethal hyperacute neurological syndrome associatedwith high blood levels of TNFα and is the most severe complicationoccurring in malaria patients. Levels of serum TNFα correlated directlywith the severity of the disease and the prognosis in patients withacute malaria attacks {Grau et al., N. Engl. J. Med. 320 (24), 1586–1591(1989)}.

Macrophage-induced angiogenesis is known to be mediated by TNFα.Leibovich et al. {Nature, 329, 630–632 (1987)} showed TNFα induces invivo capillary blood vessel formation in the rat cornea and thedeveloping chick chorioallantoic membranes at very low doses and suggestTNFα is a candidate for inducing angiogenesis in inflammation, woundrepair, and tumor growth. TNFα production also has been associated withcancerous conditions, particularly induced tumors {Ching et al., Brit.J. Cancer, (1955) 72, 339–343, and Koch, Progress in MedicinalChemistry, 22, 166–242 (1985)}.

TNFα also appears to play a role in the area of chronic pulmonaryinflammatory diseases. The deposition of silica particles leads tosilicosis, a disease of progressive respiratory failure caused by afibrotic reaction. Antibodies to TNFα completely blocked thesilica-induced lung fibrosis in mice {Pignet et al., Nature, 344:245–247(1990)}. High levels of TNFα production (in the serum and in isolatedmacrophages) have been demonstrated in animal models of silica andasbestos induced fibrosis {Bissonnette et al., Inflammation 13(3),329–339 (1989)}. Alveolar macrophages from pulmonary sarcoidosispatients have also been found to spontaneously release massivequantities of TNFα as compared with macrophages from normal donors{Baughman et al., J. Lab. Clin. Med. 115(1), 36–42 (1990)}.

TNFα is also implicated in the inflammatory response which followsreperfusion, called reperfusion injury, and is a major cause of tissuedamage after loss of blood flow {Vedder et al., PNAS 87, 2643–2646(1990)}. TNFα also alters the properties of endothelial cells and hasvarious pro-coagulant activities, such as producing an increase intissue factor pro-coagulant activity and suppression of theanticoagulant protein C pathway as well as down-regulating theexpression of thrombomodulin {Sherry et al., J. Cell Biol. 107,1269–1277 (1988)}. TNFα has pro-inflammatory activities which togetherwith its early production (during the initial stage of an inflammatoryevent) make it a likely mediator of tissue injury in several importantdisorders including but not limited to, myocardial infarction, strokeand circulatory shock. Of specific importance may be TNFα-inducedexpression of adhesion molecules, such as intercellular adhesionmolecule (ICAM) or endothelial leukocyte adhesion molecule (ELAM) onendothelial cells {Munro et al., Am. J. Path. 135 (1), 121–132 (1989)}.

TNFα blockage with monoclonal anti-TNFα antibodies has been shown to bebeneficial in rheumatoid arthritis {Elliot et al., Int. J. Pharmac. 199517(2), 141–145}. High levels of TNFα are associated with Crohn's disease{von Dullemen et al., Gastroenterology, 1995 109(1), 129–135} andclinical benefit has been achieved with TNFα antibody treatment, thusconfirming the importance of TNFα in the disease.

Moreover, it is now known that TNFα is a potent activator of retrovirusreplication including activation of HIV-1. {Duh et al., Proc. Nat. Acad.Sci. 86, 5974–5978 (1989); Poll et al., Proc. Nat. Acad. Sci. 87,782–785 (1990); Monto et al., Blood 79, 2670 (1990); Clouse et al., J.Immunol. 142, 431–438 (1989); Poll et al., AIDS Res. Hum. Retrovirus,191–197 (1992)}. AIDS results from the infection of T lymphocytes withHuman Immunodeficiency Virus (HIV). At least three types or strains ofHIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequenceof HIV infection, T-cell mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Other viruses, such as HIV-1 and HIV-2, infect T lymphocytesafter T cell activation and such virus protein expression and/orreplication is mediated or maintained by such T cell activation. Once anactivated T lymphocyte is infected with HIV, the T lymphocyte mustcontinue to be maintained in an activated state to permit HIV geneexpression and/or HIV replication. Cytokines, specifically TNFα, areimplicated in activated T-cell mediated HIV protein expression and/orvirus replication by playing a role in maintaining T lymphocyteactivation. Therefore, interference with cytokine activity such as byprevention or inhibition of cytokine production, notably TNFα, in aHIV-infected individual aids in limiting the maintenance of T lymphocyteactivation caused by HIV infection.

Monocytes, macrophages, and related cells, such as kupffer and glialcells, have also been implicated in maintenance of the HIV infection.These cells, like T cells, are targets for viral replication and thelevel of viral replication is dependent upon the activation state of thecells {Rosenberg et al., The Immunopathogenesis of HIV Infection,Advances in Immunology, 57 (1989)}. Cytokines, such as TNFα, have beenshown to activate HIV replication in monocytes and/or macrophages {Poliet al. Proc. Natl. Acad. Sci., 87, 782–784 (1990)}, therefore,prevention or inhibition of cytokine production or activity aids inlimiting HIV progression as stated above for T cells. Additional studieshave identified TNFα as a common factor in the activation of HIV invitro and has provided a clear mechanism of action via a nuclearregulatory protein found in the cytoplasm of cells (Osborn, et al., PNAS86, 2336–2340). This evidence suggests that a reduction of TNFαsynthesis may have an antiviral effect in HIV infections, by reducingthe transcription and thus virus production.

AIDS viral replication of latent HIV in T cell and macrophage lines canbe induced by TNFα {Folks et al., PNAS 86, 2365–2368 (1989)}. Amolecular mechanism for the virus inducing activity is suggested byTNFα's ability to activate a gene regulatory protein (NFκB) found in thecytoplasm of cells, which promotes HIV replication through binding to aviral regulatory gene sequence (LTR) {Osborn et al., PNAS 86, 2336–2340(1989)}. TNFα in AIDS associated cachexia is suggested by elevated serumTNFα and high levels of spontaneous TNFα: production in peripheral bloodmonocytes from patients {Wright et al, J. Immunol. 141 (1), 99–104(1988)}.

TNFα has been implicated in other viral infections, such as thecytomegalia virus (CMV), influenza virus, adenovirus, and the herpesfamily of viruses for similar reasons as those noted.

It is recognized that suppression of the effects of TNFα can bebeneficial in a variety of conditions and in the past, steroids such asdexamethasone and prednisone as well as polyclonal and monoclonalantibodies {Beutler et al., Science 234, 470–474 (1985); WO 92/11383}have been employed for this purpose. Conditions in which the inhibitionof TNFα is desirable include septic shock, sepsis, endotoxic shock,hemodynamic shock and sepsis syndrome, post ischemic reperfusion injury,malaria, mycobacterial infection, meningitis, psoriasis, congestiveheart failure, fibrotic disease, cachexia, graft rejection, cancer,autoimmune disease, opportunistic infections in AIDS, rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis and other arthriticconditions, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythrematosis, ENL in leprosy, radiation damage, asthma,and hyperoxic alveolar injury.

The suppression of the action of NFκB in the nucleus can be useful inthe treatment of a variety of diseases including but not limited torheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, otherarthritic conditions, septic shock, septis, endotoxic shock, graftversus host disease, wasting, Crohn's disease, ulcerative colitis,multiple sclerosis, systemic lupus erythrematosis, ENL in leprosy, HIV,AIDS, and opportunistic infections in AIDS.

DETAILED DESCRIPTION

The compounds of the present invention affect the levels ofphosphodiesterases, TNFα and NFκB and the method involves the regulationof the levels of phosphodiesterases, TNFα and NFκB through theadministration of compounds of the formula:

in which:

-   (a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0, 1, 2,    or 3, and R¹ is alkyl of one to 10 carbon atoms, monocycloalkyl of    up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or    benzocyclic alkyl of up to 10 carbon atoms, or-   (b) X is —CH═ and R¹ is alkylidene of up to 10 carbon atoms,    monocyloalkylidene of up to 10 carbon atoms, or bicycloalkylidene of    up to 10 carbon atoms;-   R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy,    carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,    hydroxy, amino, lower alkyl, lower alkylidenemethyl, lower alkoxy,    or halo;-   R³ is (i), phenyl, unsubstituted or substituted with 1 or more    substituents each selected independently from nitro, cyano, halo,    trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,    carbamoyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms,    acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of    1 to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of    up to 10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy:    of up to 10 carbon atoms, alkylidenemethyl of up to 10 carbon atoms,    cycloalkylidenemethyl of up to 10 carbon atoms, phenyl, or    methylenedioxy; (ii) pyridine, substituted pyridine, pyrrolidine,    imidizole, naphthalene, or thiophene; (iii) cycloalkyl of 4–10    carbon atoms, unsubstituted or substituted with 1 or more    substituents each selected independently from the group consisting    of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy,    carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino,    substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10    carbon atoms, phenyl;-   each of R⁴ and R⁵ taken individually is hydrogen or R⁴ and R⁵ taken    together are a carbon-carbon bond;-   Y is —COZ, —C≡N, or lower alkyl of 1 to 5 carbon atoms;-   Z is —OH, —NR⁶R⁶, —R⁷, or —OR⁷;-   R⁶ is hydrogen or lower alkyl; and-   R⁷ is alkyl or benzyl.

One preferred group are the compounds of Formula I in which R¹ is alkyl,monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms; X is—(CH₂)_(n)— or —O—, where n=0, 1, 2, or 3; R² is hydrogen, nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy,halo; and R⁴, R⁵, Y, Z, R⁶, and R⁷ are as therein defined.

A second preferred group of compounds are those of Formula I in which R³is (i) phenyl or naphthalene, unsubstituted or substituted with 1 ormore substituents each selected independently from nitro, cyano, halo,trifluoromnethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 5 carbon atoms, alkyl or cycloalkyl of 1 to 10 carbon atoms, alkoxyor cycloalkoxy of 1 to 10 carbon atoms; or (ii) cycloalkyl of 4 to 10carbon atoms, unsubstituted or substituted with one or more substituentseach selected independently from the group consisting of nitro, cyano,halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl.

Particularly preferred nitrites are compound of the formula:

wherein:

-   (a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0, 1, 2,    or 3, and R¹ is alkyl of up to 10 carbon atoms, monocycloalkyl of up    to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or    benzocyclic alkyl of up to 10 carbon atoms, or-   (b) X is —CH═, and R¹ is alkylidene of up to 10 carbon atoms or    monocycloalkylidene of up to 10 carbon atoms;-   R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy,    carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,    hydroxy, amino, lower alkyl, lower alkoxy, or halo; and-   R³ is (i) phenyl or naphthyl, unsubstituted or substituted with 1 or    more substituents each selected independently from nitro, cyano,    halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,    acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3    carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted    with an alkyl of 1 to 5 carbon atoms, alkoxy or cycloalkoxy of 1 to    10 carbon atoms; or (ii) cycloalkyl of 4 to 10 carbon atoms,    unsubstituted or substituted with one or more substituents each    selected independently from the group consisting of nitro, cyano,    halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,    acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted    amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon    atoms, or phenyl.

Particularly preferred alkanoic acid derivatives are compound of theformula:

wherein:

-   (a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0, 1, 2,    or 3, and R¹ is alkyl of up to 10 carbon atoms, monocycloalkyl of up    to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or    benzocyclic alkyl of up to 10 carbon atoms, or-   (b) X is —CH═, and R¹ is alkylidene of up to 10 carbon atoms or    monocycloalkylidene of up to 10 carbon atoms;-   R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy,    carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,    hydroxy, amino, lower alkyl, lower alkoxy, or halo;-   R³ is (i) phenyl or naphthyl, unsubstituted or substituted with one    or more substituents each selected independently from nitro, cyano,    halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,    acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3    carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted    with an alkyl of 1 to 5 carbon atoms, alkyl or cycloalkyl of 1 to 10    carbon atoms, alkoxy or cycloalkoxy of 1 to 10 carbon atoms; or (ii)    cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted    with one or more substituents each selected independently from the    group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy,    carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,    hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms,    alkoxy of 1 to 10 carbon atoms, or phenyl; and-   Z is —OH, —NR⁶R⁶, R⁷, or —OR⁷ in which R⁶ is hydrogen or lower    alkyl, and R⁷ is alkyl or benzyl.

The term alkyl as used herein denotes a univalent saturated branched orstraight hydrocarbon chain. Unless otherwise stated, such chains cancontain from 1 to 18 carbon atoms. Representative of such alkyl groupsare methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like. Whenqualified by “lower”, the alkyl group will contain from 1 to 6 carbonatoms. The same carbon content applies to the parent term “alkane” andto derivative terms such as “alkoxy”.

The term cycloalkyl as used herein denotes a univalent saturated cyclichydrocarbon chain. Unless otherwise stated, such chains can contain upto 18 carbon atoms. Monocyclicalkyl refers to groups having a singlering group. Polycycloalkyl denotes hydrocarbon systems containing two ormore ring systems with two or more ring carbon atoms in common.Benzocycloalkyvl signifies a monocyclicalkyl group fused to a benzogroup. Representative of monocycloalkyl groups are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl,cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, cycloheptadecyl, andcyclooctadecyl. Representative of polycycloalkyl includebicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, and bicyclo[2.2.2]octyl.Benzocycloalkyl is typified by tetrahydronaphthyl, indanyl, and1,2-benzocycloheptanyl.

The compounds can be prepared using methods which are known in generalfor the preparation of diaryl alkenes. For example, an appropriatelysubstituted bis(aryl) ketone can be treated with a dialkylcyanomethylphosphonate to yield the corresponding bis arylacrylonitrile. This can be hydrolysed to the corresponding carboxylicacid, esters and amides by methods known per se. Alternatively, thesubstituted bis(aryl) ketone can be treated with an alkyl disubstitutedphosphonoacetate or a disubstituted carbamoylmethyl-phosphonate andlithium hexamethyldisilazide to form the ester or amide, respectively,directly. The substituted bis(aryl) ketone alternatively can be treatedwith the appropriate triphenylphosphite.

The bis(aryl) ketones also are obtained by methods known per se such asfor example by Friedel-Crafts acylations with acid chlorides in thepresence of a Lewis acid.

Representative examples of these compounds include3,3-bis-(3,4-dimethoxyphenyl)-acrylonitrile,3,3-bis-(3-ethoxy-4-methoxyphenyl)acrylonitrile, methyl3,3-bis-(3-ethoxy-4-methoxyphenyl)-propenoate, methyl3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropenoate,3-(3-propoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3,3-bis-(3-cyclopentoxy-4-methoxyphenyl)acrylonitrile, methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropenoate3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropene,1-(3-cyclopentoxy-4-methoxyphenyl)-1-phenylpropane,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanoate,3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanoate,3,3-bis-(3,4-dimethoxyphenyl)propanenitrile,3,3-bis-(3-ethoxy-4-methoxyphenyl)propanenitrile,3-(3,4-dimethoxyphenyl)-3-phenylacrylonitrile,3-(3-ethoxy-4-methoxyphenyl)-3-naphthylpropanenitrile,3-(3,4-dimethoxyphenyl)-3-phenylpropanenitrile, and3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile.

A further group of preferred compounds include4,4-bis-(3,4-dimethoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-phenylbut-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-cyclopentoxy-4-methoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-indan2-yloxy-4-methoxyphenyl)but-3-en-2-one;4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)but-3-en-2-one;4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one;4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)but-3-en-2-one;4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one; methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enoate; methyl3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enoate; methyl3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanoate;4-(3-ethoxy-4-methoxyphenyl)-4-(2-furyl)but-3-en-2-one;3-(3-ethoxy-4-methoxyphenyl)-3-(2-furyl)prop-2-enenitrile;3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)but-3-en-2-one;4,4-bis-(3,4-dimethoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)butan-2-one;4,4-bis-(3-ethoxy-4-methoxyphenyl)but-3-en-2-one;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyhenyl)prop-2-enenitrile;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-prop-2-enenitrile;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pentan-3-one;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pent-1-en-3-one;1,1-bis-(3,4-dimethoxyphenyl)pentan-3-one;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-propanenitrile;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanenitrile;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enamide;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl-3-phenyl)propanamide;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanamide;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enamide;3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)prop-2-enamide;3,3-bis-(3-ethoxy-4-methoxyphenyl)prop-2-enamide;3,3-bis-(3,4-dimethoxyphenyl)prop-2-enamide;3,3-bis-(3-ethoxy-4-methoxyphenyl)propanamide;3,3-bis-(3,4-dimethoxyphenyl)propanamide;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-exo-norbornyloxyphenyl)but-3-en-2-one;3-(3,4-dimethoxyphenyl)-3-(4-methoxy-3-exo-norbornyloxyphenyl)prop-2-enenitrile;3-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)prop-2-enenitrile;3-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile; and3-(4-aminophenyl)-3-(3-ethoxy-4-dimethoxyphenyl)prop-2-enenitrile.

These compounds may possess one or more centers of chirality and thuscan exist as optical isomers. Both the racemates of these isomers andthe individual isomers themselves, as well as diastereoisomers whenthere are two or more chiral centers, are within the scope of thepresent invention. The racemates can be used as such or can be separatedinto their individual isomers mechanically as by chromatography using achiral absorbent. Alternatively, the individual isomers can be preparedin chiral form or separated chemically from a mixture by forming saltswith a chiral acid, such as the individual enantiomers of10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid,methoxyacetic acid, tartaric acid, diacetyltartaric acid, malic acid,pyrrolidone-5-carboxylic acid, and the like, and then freeing one orboth of the resolved bases, optionally repeating the process, so as toobtain either or both isomers substantially free of the other; i.e., ina form having an optical purity of >95%. In addition, the compounds inwhich R⁴ and R⁵ taken together are a carbon-carbon bond can exist as cis(Z) and trans (E) isomers.

The compounds can be used, under the supervision of qualifiedprofessionals, to inhibit the undesirable effects of TNFα, NFκB, andphosphodiesterase. The compounds can be administered orally, rectally,or parenterally, alone or in combination with other therapeutic agentsincluding antibiotics, steroids, etc., to a mammal in need of treatment.Oral dosage forms include tablets, capsules, dragees, and similarshaped, compressed pharmaceutical forms. Isotonic saline solutionscontaining 20–100 milligrams/milliliter can be used for parenteraladministration which includes intramuscular, intrathecal, intravenousand intraarterial routes of administration. Rectal administration can beeffected through the use of suppositories formulated from conventionalcarriers such as cocoa butter.

Dosage regimens must be titrated to the particular indication, the age,weight, and general physical condition of the patient, and the responsedesired but generally doses will be from about 1 to about 1000milligrams/day as needed in single or multiple daily administration. Ingeneral, an initial treatment regimen can be copied from that known tobe effective in interfering with TNFα activity for other TNFα mediateddisease states by the compounds of the present invention. Treatedindividuals will be regularly checked for T cell numbers and T4/T8ratios and/or measures of viremia such as levels of reversetranscriptase or viral proteins, and/or for progression ofcytokine-mediated disease associated problems such as cachexia or muscledegeneration. If no effect is observed following the normal treatmentregimen, then the amount of cytokine activity interfering agentadministered is increased, e.g., by fifty percent a week.

The compounds of the present invention can also be used topically in thetreatment or prophylaxis of topical disease states mediated orexacerbated by excessive TNFα production, such as viral infections, forexample those caused by the herpes viruses or viral conjunctivitis,psoriasis, other skin disorders and diseases, etc.

The compounds can also be used in the veterinary treatment of mammalsother than humans in need of prevention or inhibition of TNFαproduction. TNFα mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those notedabove, but in particular viral infections. Examples include felineimmunodeficiency virus, equine infectious anaemia virus, caprinearthritis virus, visna virus, and maedi virus, as well as otherlentiviruses.

Inhibition of PDE III, PDE IV, TNFα and NFκB by these compounds can beconveniently assayed using methods known in the art, e.g., enzymeimmunoassay, radioimmunoassay, immunoelectrophoresis, affinity labeling,etc., of which the following are typical.

Enzyme-linked Immunosorbent Assay for TNFα

PBMC isolation: PBMC from normal donors were obtained by Ficoll-Hypaquedensity centrifugation. Cells were cultured in RPMI supplemented with10% AB+ serum, 2 mM L-glutamine, 100 U/mL penicillin and 100 mg/mLstreptomycin.

PBMC suspensions: Drugs were dissolved in dimethylsulfoxide (SigmaChemical), further dilutions were done in supplemented RPMI. The finaldimethylsulfoxide concentration in the presence or absence of drug inthe PBMC suspensions was 0.25 wt %. Drugs were assayed at half-logdilutions starting at 50 mg/mL. Drugs were added to PBMC (10⁶ cells/mL)in 96 wells plates one hour before the addition of LPS.

Cell stimulation: PBMC (10⁶ cells/mL) in the presence or absence of drugwere stimulated by treatment with 1 mg/mL of LPS from SalmonellaMinnesota R595 (List Biological Labs, Campbell, Calif.). Cells were thenincubated at 37° C. for 18–20 hours. Supernatants were then harvestedand assayed immediately for TNFα levels or kept frozen at −70° C. (fornot more than 4 days) until assayed.

TNFα Determination: The concentration of TNFα in the supernatant wasdetermined by human TNFα ELISA kits (ENDOGEN, Boston, Mass.) accordingto the manufacturer's directions.

Phosphodiesterase can be determined in conventional models. For example,using the method of Hill and Mitchell, U937 cells of the humanpromonocytic cell line are grown to 1×10⁶ cells/mL and collected bycentrifugation. A cell pellet of 1×10⁹ cells is washed in phosphatebuffered saline and then frozen at −70° C. for later purification orimmediately lysed in cold homogenization buffer (20 mM Tris-HCl, pH 7.1,3 mM 2-mercaptoethanol, 1 mM magnesium chloride, 0.1 mM ethyleneglycol-bis-(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 1 μMphenylmethylsulfonyl fluoride (PMSF), and 1 μg/mL leupeptin). Cells arehomogenized with 20 strokes in a Dounce homogenizer and supernatantcontaining the cytosolic fraction are obtained by centrifugation. Thesupernatant then is loaded onto a Sephacryl S-200 column equilibrated inhomogenization buffer. Phosphodiesterase is eluted in homogenizationbuffer at a rate of approximately 0.5 mL/min and fractions are assayedfor phosphodiesterase activity −/+ rolipram. Fractions containingphosphodiesterase activity (rolipram sensitive) are pooled and aliquotedfor later use.

The phosphodiesterase assay is carried out based on procedure describedby Hill and Mitchell. The assay is carried out in a total volume of 100μl containing various concentration of test compounds, 50 mM Tris-HCl,pH 7.5, 5 mM magnesium chloride and 1 μM cAMP of which 1% was ³H cAMP.Reactions are incubated at 30° C. for 30 minutes and terminated byboiling for 2 minutes. The amount of phosphodiesterase IV containingextract used for these experiments is predetermined such that reactionsare within the linear range and consumed less than 15% of the totalsubstrate. Following termination of reaction, samples are chilled at 4°C. and then treated with 10 μl 10 mg/mL snake venom for 15 min at 30° C.Unused substrate then is removed by adding 200 μl of a quaternaryammonium ion exchange resin (AG1-X8, BioRad) for 15 minutes. Samplesthen are spun at 3000 rpm, 5 min and 50 μl of the aqueous phase aretaken for counting. Each data point is carried out in duplicate andactivity is expressed as percentage of control. The IC₅₀ of the compoundthen is determined from dose response curves of a minimum of threeindependent experiments.

The following examples will serve to further typify the nature of thisinvention but should not be construed as a limitation in the scopethereof, which scope is defined solely by the appended claims.

EXAMPLE 1 3,3-bis-(3,4-Dimethoxyphenyl)acrylonitrile

A. 3,4,3′,4,′-Tetramethoxybenzophenone

To a stirred ice bath cooled solution of veratole (2.07 g, 15.0 mmol) in30 mL of methylene chloride under nitrogen was added aluminum chloride(2.20 g, 16.5 mmol). A slight exotherm resulted. To the reaction mixturewas then added 3,4-dimethoxybenzoyl chloride (3.01 g, 15.0 mmol) and 20mL of methylene chloride. The reaction was then allowed to warm to roomtemperature and then refluxed for 3.5 hours and then allowed to stir atroom temperature for 16 hours. The reaction mixture was then poured into50 mL of ice water and stirred for 15 minutes. This mixture wasextracted with methylene chloride (2×25 mL each). The combined extractswere dried over sodium sulfate and concentrated in vacuo to afford thecrude product as a tan solid. The crude product was purified by flashchromatography (silica gel, 4/96 ethyl acetate/methylene chloride) toafford 2.97 g (66%) of the product as a white powder: ¹H NMR (CDCl₃) δ7.4 (m, 4H), 6.91 (m, 2H), 3.97 (s, 6H), 3.95 (s, 6H); ¹³C NMR (DMSO-d₆)δ 194.4, 152.5, 148.8, 130.7, 124.7, 112.2, 109.7, 56.0. Anal. Calcd forC₁₇H₁₈O₅. Theoretical: C, 67.54; H, 6.00. Found: C, 67.42; H, 6.03.

B. 3,3-bis-(3′,4′-Dimethoxyphenyl)acrylonitrile

To an ice bath cooled stirred suspension of sodium hydride (5.0 mmol) in20 mL of tetrahydrofuran was added 0.8 mL of diethylcyanomethylphosphonate dropwise via syringe. The mixture was allowed towarm to room temperature and then 3,4,3′,4,′-tetramethoxybenzophenone(1.51 g, 5.00 mmol) and 10 mL of tetrahydrofuran were added. The mixturewas stirred for 5 days and then quenched with 100 mL of H₂O. Thereaction mixture was then extracted with methylene chloride (50 mL and25 mL). The combined extracts were dried over sodium sulfate andconcentrated to afford the crude product as an oil. The crude productwas purified by flash chromatography to afford the product as a whitewax: ¹H NMR (CDCl₃) δ 7.95 (br m, 6H), 5.57 (s, 1H), 3.94 (s, 3H), 3.92(s, 3H), 3.87 (s, 3H), 3.84 (s, 3H); ¹³C NMR (DMSO-d₆) δ 162.4, 151.0,150.5, 148.8, 148.5, 131.8, 129.5, 123.2, 122.2, 118.6, 112.7, 111.4,110.7, 110.7, 91.9, 56.0, 55.9, 55.9.

EXAMPLE 2 cis and trans3-(3,4-Dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)acrylonitrile

A. 3,4-Dimethoxy-3-ethoxy-4-methoxybenzophenone

To an ice bath cooled stirred suspension of 3-ethoxy-4-methoxybenzoicacid (0.98 g, 5.0 mmol) in 20 mL methylene chloride was added oxalylchloride (0.44 mL, 5.0 mmol) and 2 drops of N,N dimethylformamide(dimethylformamide). The resulting yellow mixture was stirred at roomtemperature for 35 minutes at which time a solution had formed. Thesolution was cooled in an ice bath and veratrole (0.64 mL, 5.0 mmol) wasadded followed by aluminum chloride (0.73 g, 5.5 mmol). The ice bath wasremoved and the mixture was stirred at room temperature. The reactionwas monitored by HPLC (Waters Nova-Pak/C,8 column 3.9×150 mm, 4 micron,1 mL/min, 35/65 acrylonitrile/0.1% aqueous phosphoric acid and after 37hours the reaction was complete. The reaction mixture was poured into 30mL of ice, stirred for 30 minutes and was then extracted with methylenechloride (3×20 mL). The methylene chloride extracts were washedsuccessively with aqueous sodium bicarbonate (30 mL), water (2×50 mL)and brine (50 mL). The organic layer was then dried over magnesiumsulfate, filtered and concentrated in vacuo to afford 1.05 g of a brownsolid. The crude product was purified by flash column chromatography(silica gel, 5% ethyl acetate/methylene chloride) and the resultingproduct was then dried in vacuo (60° C.,<1 mmHg) to afford 0.8 g (51%)of the product: mp 122–124.5° C.; ¹H NMR (CDCl₃) δ 7.48–7.34 (m, 4H),6.98–6.86 (m, 2H), 4.16 (q, J=7 Hz, 2H), 3.96 (s, 3H), 3.96 (s, 3H),3.94 (s, 3H), 1.49 (t, J=7 Hz, 3H); ¹³C NMR (CDCl₃) δ 194.4, 152.8,152.5, 148.8, 148.0, 130.7, 130.6, 124.6, 124.5, 113.5, 112.2, 109.9,109.7, 64.3, 55.9, 55.9, 14.6; HPLC (Waters Nova-Pak/C,8 column, 3.9×150mm, 4 micron, 1 mL/min, 35/65 acrylonitrile/0.1% aqueous phosphoric acid8 min, 99%; Anal. Calcd for C₁₈H₂₀O₅. Theoretical: C, 68.34, H, 6.37.Found: C, 68.56; H, 6.51.

B. cis and trans3-(3,4-Dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)acrylonitrile

To an ice bath cooled stirred solution of diethylcyanomethylphosphonate(0.9 mL, 5.5 mmol) in 15 mL of tetrahydrofuran was added a 1.3 Msolution of lithium hexamethyldisilazide (4.2 mL, 5.5 mmol) intetrahydrofuran. The solution was allowed to warm to room temperatureand was stirred for 30 minutes and then a slurry of3,4-dimethoxy-3-ethoxy-4-methoxybenzophenone (1.58 g, 5.00 mmol) in 20mL of tetrahydrofuran was added. The reaction mixture was stirred atroom temperature for 21 hours and was then quenched with 100 mL ofwater. The resulting mixture was extracted with methylene chloride (2×50mL). The combined extracts were washed with water, chied over magnesiumsulfate, and concentrated in vacuo to afford the crude product as anorange oil. The crude product was purified by flash columnchromatography (silica gel, 3% ethyl acetate/methylene chloride) andthen recrystallized from hexane/ethyl. The resulting product was thendried in vacuo (40° C.,<1 mmHg) to afford 0.6 g (35%) of a white solid:mp 103–106° C.; ¹H NMR (CDCl₃) δ 7.10–6.75 (m, 6H), 5.55 (s, 1H),4.17–3.76 (m, 1H), 1.54–1.36 (m, 3H); ¹³C NMR (CDCl₃) δ 162.5, 151.0,150.8, 150.5, 148.8, 148.6, 148.1, 147.8, 131.9, 131.7, 129.6, 129.5,123.2, 123.1, 122.1, 122.0, 118.6, 114.2, 112.9, 112.8, 111.4, 110.9,110.9, 110.7, 110.7, 91.8, 64.5, 56.0, 55.9, 14.6; HPLC (WatersNova-Pak/C,8 column, 3.9×150 mm, 4 micron, 1 mL/min, 45/55acrylonitrile/0.1% aqueous phosphoric acid 7 min, 100%; Anal. Calcd forC₂₀H₂₁NO₄. Theoretical: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.62; H,6.21; N, 4.07.

EXAMPLE 3 3-(3,4-Dimethoxyphenyl)-3-phenylacetate

A. 3,4-Dimethoxybenzophenone

3,4-Dimethoxybenzophenone was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (2 mL, 15 mmol),aluminum chloride (2.2 g, 16.5 mmol) and benzoyl chloride (1.8 mL, 15.5mmol). The crude mixture was purified by flash column chromatography(silica gel, 3% ethyl acetate/methylene chloride) to yield 3.44 g (93%)of the product as a white solid: mp 99–100° C.; ¹H NMR (CDCl₃) δ7.82–7.30 (m, 7H), 6.95–6.85 (m, 1H), 3.96 (s, 3H), 3.94 (s, 3H); ¹³CNMR (CDCl₃) δ 195.5, 153.0, 149.0, 138.2, 131.8, 130.2, 129.6, 128.1,125.4, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C₁₅H₁₄O₃. Theoretical:C, 74.36; H, 5.82. Found: C, 74.21; H, 6.01.

B. 3-(3,4-Dimethoxyphenyl)-3-phenylacetate (E and Z Isomers)

3-(3,4-Dimethoxyphenyl)-3-phenylacetate was prepared analogously to3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxybenzophenone(4.8 g, 20 mmol), trimethylphosphonoacetate (4.1 g, 22 mmol) and lithiumhexamethyldisilazide (22 mL, 22 mmol, 1M) with a reaction time of 138hours at reflux. The crude mixture was purified by flash columnchromatography (silica gel, 1% ethyl acetate/methylene chloride) toafford 14.39 g (73%) of a mixture of the E and Z isomers as an oil. Theisomers were separated by additional purification (silica gel, 1% ethylacetate/methylene chloride) to afford pure samples of each of theisomers.

Isomer 1: ¹H NMR (CDCl₃) δ 7.40–7.36 (m, 3H), 7.26–7.20 (m, 2H), 6.88(s, 1H), 6.80 (s, 2H), 6.30 (s, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.60(s, 3H); ¹³C NMR (CDCl₃) δ 166.5, 156.9, 150.4, 148.7, 138.9, 133.4,129.1, 128.1, 128.0, 127.8, 122.1, 114.9, 110.8, 110.6, 55.9, 55.8,51.1; Anal. Calcd for C₁₈H₁₈O₄. Theoretical: C, 72.47; H, 6.08. Found:C, 72.08; H, 6.11.

Isomer 2: ¹H NMR (CDCl₃) δ 7.35–7.32 (m, 5H), 6.90–6.83 (m, 2H), 6.73(s, 1H), 6.30 (s, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.64 (s, 3H); ¹³C NMR(CDCl_(3) δ) 166.6, 156.7, 149.2, 148.3, 141.2, 131.1, 129.4, 128.5,128.3, 122.4, 116.4, 112.7, 110.4, 55.8, 55.7, 51.2; Anal. Calcd forC₁₈H₁₈O₄. Theoretical: C, 72.47; H, 6.08. Found: C, 72.28; H, 5.94.

EXAMPLE 4 3-Phenyl-3-(3′-ethoxy-4-methoxyphenyl)acrylamide (E and ZIsomers)

The acrylamide was prepared analogously to3,3-bis-(3,4-dimethoxyphenyl)acrylate using3-ethoxy-4-methoxybenzophenone (0.3 g, 1.2 mmol),diethylcarbamoylmethyl-phosphonate (0.25 g, 1.3 mmol) and lithiumhexamethyldisilazide (1 mL, 1.3 mmol, 1.3M) with a reaction time of 54hours at reflux. The crude mixture was purified by flash columnchromatography (silica gel, 45% ethyl acetate/methylene chloride) toafford 0.06 g (17%) of a mixture of the E and Z isomers as an oil: ¹HNMR (CDCl₃) δ 7.54–7.19 (m, 10H), 7.00–6.65 (m, 6H), 6.34 (s, 2H), 5.54(s, 1H), 5.55 (s, 1H), 5.24 (s, 1H), 5.04 (s, 1H), 4.16 (m, 4H), 3.92(s, 3H), 3.87 (s, 3H), 1.60–1.33 (m, 6H); ¹³C NMR (CDCl₃) δ 168.7,168.6, 150.8, 150.4, 149.7, 148.4, 148.0, 140.7, 138.2, 133.0, 130.2,129.2, 129.1, 128.8, 128.3, 128.0, 121.9, 121.6, 120.0, 113.7, 111.9,111.4, 110.8, 64.4, 64.3, 55.9, 14.6; Anal. Calcd for C₁₈H₁₉NO₃.0.35H₂O.Theoretical: C, 71.19; H, 6.54; N, 4.61. Found: C, 71.19; H, 6.68; N,4.45.

EXAMPLE 5 1-(3,4-Dimethoxyphenyl)-1-phenylprop-1-ene (E and Z Isomers)

1-(3,4-Dimethoxyphenyl)-1-phenylprop-1-ene was prepared analogously tomethyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using3,4-dimethoxybenzophenone (3 g, 12.4 mmol), (ethyl)triphenylphosphoniumbromide (5.1 g, 13.6 mmol) and lithium hexamethyldisilazide (13.6 mL,13.6 mmol, 1M) with a reaction time of 4 hours at room temperature. Thecrude mixture was purified by flash column chromatography (silica gel,10% hexane/methylene chloride) to afford 1.3 g (41%) of a mixture of theE and Z isomers as a white solid: mp 72–73° C.; ¹H NMR (CDCl₃) δ7.40–6.80 (m, 16H), 6.16–6.08 (m, 2H), 3.90–3.80 (m, 12H), 1.97–1;73 (m,6H); ¹³C NMR (CDCl₃) δ 148.6, 148.5, 148.1, 147.8 142.9, 142.3, 142.0,140.0, 136.0, 132.5, 129.9, 128.0, 128.0, 127.1, 126.7, 126.6, 123.8,122.6, 122.5, 119.8, 113.6, 110.8, 110.7, 110.4, 55.8, 55.8, 55.7, 15.7,15.5; Anal. Calcd for C₁₇H₁₈O₂. Theoretical: C, 80.28; H, 7.13. Found:C, 79.94; H, 7.12.

EXAMPLE 6 1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)prop-1-ene(E and Z Isomers)

1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)prop-1-ene wasprepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylateusing 3,4-dimethoxy-3′-ethoxy-4′-methoxybenzophenone (1.6 g, 5 mmol),(ethyl)triphenylphosphonium bromide (2.04 g, 5.5 mmol) and lithiumhexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24hours at room temperature. The crude mixture was purified by flashcolumn chromatography (silica gel, 10% hexane/methylene chloride) toafford 0.8 g (49%) of a mixture of the E and Z, isomers as a whitesolid: mp 65.5–68° C.; ¹H NMR (CDCl₃) δ 6.95–6.65 (m, 12H), 6.14–6.00(m, 2H), 4.11–3.78 (m, 22H), 1.86–1.74 (m, 6H), 1.50–1.36 (m, 6H); ¹³CNMR (CDCl₃) δ 148.5, 148.4, 148.1, 147.7, 141.8, 141.7, 136.1, 136.0,132.6; 132.5, 122.5, 122.3, 119.7, 114.7, 113.1, 111.9, 111.0, 110.7,110.4, 55.9, 55.8, 55.8, 55.7, 15.7, 14.7; Anal. Calcd for C₂₀H₂₄O₄.Theoretical: C, 73.15; H, 7.37. Found: C, 73.33; H, 7.39.

EXAMPLE 7 1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)but-1-ene(E and Z Isomers)

1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)but-1-ene wasprepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylateusing 3,4-dimethoxy-3′-ethoxy-4′-methoxybenzophenone (1 g, 3.2 mmol),propyltriphenylphosphonium bromide (1.34 g, 3.5 mmol) and lithiumhexamethyldisilazide (2.7 mL, 3.5 moll, 1.3M) with a reaction time of2.5 hours at room temperature. The crude mixture was purified bychromatography (silica gel, methylene chloride) followed by a Kugelrohr,distillation to yield 0.77 g (71%) of a mixture of the E and Z, isomersas an oil: ¹H NMR (CDCl₃) δ 6.92–6.65 (m, 12H), 6.02–5.89 (m, 2H),4.12–3.96 (m, 4H), 3.92 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 3.85 (s,3H), 3.82 (s, 3H), 3.81 (s, 3H), 2.22–2.04 (m, 4H), 1.51–1.38 (m, 6H),1.14–0.98 (m, 6H); ¹³C NMR (CDCl₃) δ 148.5, 148.1, 147.8, 147.7, 140.4,140.4, 136.0, 135.9, 133.0, 132.9, 130.1, 130.0, 122.2, 119.8, 114.6,113.1, 112.0, 111.0, 110.7, 110.4, 64.3, 64.2, 55.9, 23.2, 14.8, 14.7;Anal. Calcd for C₂₁H₂₆O₄. Theoretical: C, 73.66; H, 7.65. Found: C,73.32; H, 7.26.

EXAMPLE 8 3-(3-Ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile (E and ZIsomers)

3-(3-Ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile was preparedanalogously to 3,3-bis-(3,4-dimethoxyphenyl)acrylate using3-ethoxy-4-methoxybenzophenone (1.3 g, 5 mmol),diethylcyanomethylphosphonate (0.9 mL, 5.5 mmol) and lithiumhexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24hours at room temperature. The crude mixture was purified by flashcolumn chromatography (silica gel, methylene chloride) to afford 1.35 g(96%) of a mixture of the E and Z isomers as a white solid: mp 74–77°C.; ¹H NMR (CDCl₃) δ 7.50–7.24(m, 10H), 7.07–6.75 (m, 6H), 5.60 (s, 1H),4.15–3.95 (m, 4H), 3.92 (s, 3H), 3.89 (s, 3H), 1.50–1.36 (m, 6H); ¹³CNMR (CDCl₃) δ 162.8, 162.7, 151.4, 150.9, 148.1, 147.1, 147.9, 139.3,137.1, 131.3, 130.2, 129.9, 129.5, 129.3, 128.6, 128.5, 128.4, 123.1,122.0, 118.3, 118.2, 113.9, 112.5, 110.9, 93.3, 92.9, 64.4, 55.9, 55.9,14.6; Anal. Calcd for C₁₈H₁₇NO₂. Theoretical: C, 77.40; H, 6.13; N,5.01. Found: C, 77.14; H, 6.06; N, 4.75.

EXAMPLE 9 3-(3-Ethoxy-4-methoxyphenyl)-3-phenylpropionitrile

To a solution of 3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile (0.9g, 3.2 mmol) in a mixture of ethanol and ethyl acetate (20 mL/30 mL) wasadded 0.5 g of 10% palladium on carbon catalyst in portions. The mixturewas hydrogenated in a Parr-Shaker apparatus at 55–60 psi of hydrogen for12 days. The reaction mixture was filtered through celite and thefiltrate was concentrated in vacuo to afford the crude product. Thecrude product was purified by flash column chromatography (silica gel,4% hexane/methylene chloride) to afford 0.15 g (15%) of the product asan oil: ¹H NMR (CDCl₃) δ 7.40–7.16 (m, 5H); 6.88–6.78 (m, 3H), 4.32 (t,J=7.5 Hz, 1H), 4.03 (q, J=7 Hz, 2H), 3.85 (s, 3H), 3.00 (d, J=7.5 Hz,2H), 1.42 (t, J=7 Hz, 3H); ¹³ C NMR (CDCl₃) δ 148.7, 148.5, 141.5,133.7, 128.8, 127.4, 127.3, 119.5, 118.5, 112.7, 111.6, 64.4, 55.9,46.7, 24.5, 14.7; Anal. Calcd for C₁₈H₁₇NO₂. Theoretical: C, 76.84; H,6.81; N, 4.98. Found: C, 76.53; H, 6.92; N, 4.95.

EXAMPLE 103-(3,4-Dimethoxyphenyl)-3-(3′,5′-dimethoxyphenyl)acrylonitrile (E and ZIsomers)

A. 3,4,3′,5′-Tetramethoxybenzophenone

3,4,3′,5′-Tetramethoxybenzophenone was prepared analogously to4-(3,4-dimethoxybenzoyl)pyridine using butyl lithium (9 mL, 22 mmol,2.5M), 4-bromoveratrole (2.9 mL, 20 mmol) and 3,5-dimethoxybenzonitrile(3.75 g, 23 mmol). The crude product was purified by flash columnchromatography (silica gel, methylene chloride) to afford 1.54 g (26%)of the product: mp 107–110° C.; ¹H NMR (CDCl₃) δ 7.53–7.39 (m, 2H),6.95–6.84 (m, 3H), 6.70–6.60 (m, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.83(s, 6H); ¹³C NMR (CDCl₃) δ 195.0, 160.4, 153.0, 148.9, 140.1, 130.0,125.4, 112.0, 109.7, 107.5, 104.1, 56.0, 55.5; Anal. Calcd for C₁₇H₁₈O₅.Theoretical: C, 67.54; H, 6.00. Found: C, 67.38; H, 5.96.

B. 3-(3,4-Dimethoxyphenyl)-3-(3′,5′-dimethoxyphenyl)acrylonitrile

3-(3,4-Dimethoxyphenyl)-3-(3′,5′-dimethoxyphenyl)acrylonitrile wasprepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylateusing 3,4,3′,5′-tetramethoxybenzophenone (0.7 g, 2.3 mmol),diethylcyanomethylphosphonate (0.42 mL, 2.5 mmol) and lithiumhexamethyldisilazide (1.9 mL, 2.5 mmol, 1.3M) with a reaction time of 60hours at room temperature. The crude product was purified by flashchromatography (silica gel, 1% ethyl acetate/methylene chloride) toafford 0.66 g (81%) of a mixture of the E and Z isomers as a whitesolid: mp 88–90° C.; ¹H NMR (CDCl₃) δ 7.10–6.80 (m, 6H), 6.61–6.40 (m,6H), 5.66 (s, 1H), 5.61 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H) 3.87 (s,3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.77 (s, 6H); ¹³C NMR (CDCl₃) δ 162.7,162.5, 160.7, 160.6, 151.1, 150.6, 148.8, 148.5, 141.3, 138.9, 131.1,129.2, 123.2, 122.1, 118.2, 118.0, 112.6, 110.9, 110.7, 110.7, 107.6,107.0, 102.1, 102.0, 93.4, 93.1, 56.0, 55.9, 55.5, 55.4; Anal. Calcd forC₁₉H₁₉NO₄. Theoretical: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.33; H,5.89; N, 4.03.

EXAMPLE 11 3-(3,4-Dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile

A. 3,4-Dimethoxy-3′-nitrobenzophenone

To a stirred ice bath cooled solution of veratrole (2.55 mL, 20 mmol) inmethylene chloride (30 mL) under nitrogen was added aluminum chloride(2.93 g, 22 mmol). A slight exotherm resulted. To the resulting mixturewas added 3-nitrobenzoyl chloride (3.8 g, 20 mmol) in 30 mL of methylenechloride., The reaction was then allowed to warm to room temperature andfollowed by heating to refluxed. After 5 hours at reflux the reactionmixture was allowed to cool to room temperature and stirred for 72hours. The reaction mixture was then poured into 100 mL of iced waterand stirred for 20 minutes. This mixture was extracted with CH₂Cl₂ (3×60mL). The organic layer was dried over magnesium sulfate and concentratedin vacuo to afford the crude product as a green solid. The crude productwas purified by flash column chromatography (silica gel, CH₂Cl₂) toafford 2.21 g (39%) of the product as a yellow solid: mp 133–135° C.; ¹HNMR (CDCl₃) δ 8.64–8.56 (m, 1H), 8.49–8.39 (m, 1H), 8.10–8.05 (m, 1H),7.76–7.65 (m, 3H), 7.55–7.47 (m, 1H), 7.36–7.29 (m, 1H), 7.00–6.87 (m,1H), 3.99 (s, 3H), 3.97 (s, 3H), ¹³C NMR (CDCl₃) δ 192.8, 153.8, 149.4,147.9, 139.7, 135.2, 129.5, 128.9, 126.2, 125.6, 124.4, 11.8, 110.0,56.2, 56.1; Anal. Calcd for C₁₅H₁₃NO₅. Theoretical: C, 62.72; H, 4.56;N, 4.88. Found: C, 62.74; H, 4.59; N, 4.89.

B. 3-(3,4-Dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile

3-(3,4-Dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile was preparedanalogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using3,4-dimethoxy-3′-nitrobenzophenone (1.44 g, 5 mmol),diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithiumhexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24hours at room temperature. The crude product was purified by flashchromatography (silica gel, 3% hexane/methylene chloride) to afford.1.12 g (72%) of a mixture of the E and Z isomers as a yellow solid: mp117.5–120° C.; ¹H NMR (CDCl₃) δ 8.40–8.17 (m, 4H), 7.90–7.55 (m, 4H),7.08–6.89 (m, 6H), 5.84 (s, 1H), 5.71(s, 1H), 3.95 (s, 3H), 3.92 (s,3H), 3.88 (s, 3H), H), 3.85 (s, 3H); ¹³CNMR (CDCl₃) δ 160.2, 160.1,151.7, 151.1, 149.2, 148.3, 148.2, 141.0, 138.8, 135.4, 134.4, 129.9,129.7, 129.7, 128.1, 124.8, 124.6, 124.4, 123.3, 123.1, 122.3, 117.4,117.3, 112.3, 111.0, 110.4, 95.7, 94.8, 56.0, 55.9; Anal. Calcd forC₁₇H₁₄N₂O₄. Theoretical: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.57; H,4.64; N, 8.92.

EXAMPLE 12 3-(3′-Aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile (Eand Z Isomers)

To a solution of 3-(3,4-dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile(0.7 g, 2.3 mmol) in 40 mL of ethyl acetate was added 0.1 g of 10%palladium on carbon catalyst. The mixture was hydrogenated in aParr-Shaker apparatus at 55–60 psi of hydrogen for 2.5 hours. Thereaction mixture was filtered through celite and the filtrate wasconcentrated in vacuo to afford the crude product. The crude product waspurified by flash column chromatography (silica gel, 15% ethylacetate/methylene chloride) to afford 0.25 g (56%) of a mixture of the Eand Z isomers as a yellow solid: mp 100–101° C.; ¹H NMR (CDCl₃) δ7.30–6.59 (m, 14H); 5.63 (s, 1H), 5.59 (s, 1H), 3.94 (s, 3H), 3.91 (s,3H), 3.87 (s, 3H), 3.84 (s, 3H); ¹³C NMR (CDCl₃) δ 163.1, 162.9, 151.1,150.5, 148.8, 148.7, 146.5, 146.4, 140.4, 138.2, 131.5, 129.5, 129.5,129.4, 123.2, 122.1, 119.9, 119.0, 118.4, 118.2, 116.8, 116.6, 115.9,115.0, 112.7, 111.0, 110.7, 93.3, 92.7, 56.1, 56.0, 55.9; Anal. Calcdfor C₁₇H₁₆N₂O₃. Theoretical: C, 72.84; H, 5.75; N, 9.99. Found: C,72.48; H, 6.05; N, 9.58.

EXAMPLE 13 3,4-Dimethoxy-3′-aminobenzophenone

To a solution of 3,4-dimethoxy-3′-nitrobenzophenone (0.5 g, 1.7 mmol) in40 mL of ethyl acetate was added 0.05 g of 10% palladium on carboncatalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at55–60 psi of hydrogen for 1.5 hours. The reaction mixture was filteredthrough celite and the filtrate was concentrated in vacuo to afford thecrude product. The crude product was purified by flash columnchromatography (silica gel, 10% ethyl acetate/methylene chloride) toafford 0.17 g (38%) of the product as a yellow solid: mp 157–175° C.; ¹HNMR (CDCl₃) δ 7.56–6.80 (m, 7H); 3.95 (s, 3H), 3.94 (s, 3H); ¹³C NMR(CDCl₃) δ 195.7, 152.9, 148.9, 146.4, 139.3, 130.3, 128.9, 125.4, 120.1,118.4, 115.6, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C₁₅H₁₅NO₃ .Theoretical: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.00; H, 6.10; N,5.13.

EXAMPLE 14 3-(3,4-Dimethoxyphenyl)-3-(4-nitrophenyl)acrylonitrile (E andZ Isomers)

A. 3,4-Dimethoxy-4′-nitrobenzophenone

3,4-Dimethoxy-4′-nitrobenzophenone was prepared analogously to3,4-dimethoxy-3′-nitrobenzophenone using veratrole (3.8 mL, 30 mmol),aluminum chloride (4.4 g, 33 mmol) and 4-nitrobenzoyl chloride (5.7 g,30 mmol) with a reaction time of 48 hours at reflux. The crude mixturewas purified by flash column chromatography (silica gel, 4% ethylacetate/methylene chloride) to afford 1.69 g (78%) of the product as awhite solid: mp 172–173° C.; ¹H NMR (CDCl₃) δ 8.43–8.31 (m, 2H),7.97–7.86 (m, 2H), 7.55–7.46 (m, 1H), 7.40–7.30 (m, 0.1H), 7.00–6.89 (m,1H), 3.99 (s, 3H), 3.96 (s, 3H); ¹³C NMR (CDCl₃) δ 193.4, 153.8, 149.4,149.3, 143.8, 130.2, 130.0, 125;8, 123.4, 111.7, 109.9, 56.1, 56.0;Anal. Calcd for C₁₅H₁₃NO₅. Theoretical: C, 62.72; H, 4.56; N, 4.88.Found: C, 62.49; H, 4.68; N, 4.86.

B. 3-(3,4-Dimethoxyphenyl)-3-(4′-nitrophenyl)acrylonitrile

3-(3,4-Dimethoxyphenyl)-3-(4′-nitrophenyl)acrylonitrile was preparedanalogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using3,4-dimethoxy-4′-nitrobenzophenone (4 g, 14 mmol),diethylcyanomethylphosphonate (2.5 mL, 15.4 mmol) and lithiumhexamethyldisilazide (11.8 mL, 15.4 mmol, 1.3M) with a reaction time of17 hours at room temperature. The crude product was purified bychromatography (silica gel, 3% hexane/methylene chloride) to afford 2.38g (55%) of a mixture of the E and Z isomers as a yellow solid: mp117.5–120° C.; ¹H NMR (CDCl₃) δ 8.40–8.20 (m, 4H), 7.70–7.46 (m, 4H),7.06–6.75 (m, 6H), 5.84 (s, 1H), 5.70 (s, 1H), 3.95 (s, 3H), 3.93 (s,3H), 3.88 (s, 3H), 3.85 (s, 3H); ¹³C NMR (CDCl₃) δ 160.3, 151.7, 151.1,149.2, 148.9, 148.7, 148.5, 148.5, 143.5, 130.6, 129.9, 129.6, 128.2,123.7, 123.1, 122.2, 117.4, 117.3, 112.3, 111.0, 110.5, 96.2, 94.9,56.0, 56.0; Anal. Calcd for C₁₇H₁₄N₂O₄. Theoretical: C, 65.80; H, 4.55;N, 9.03. Found: C, 65.45; H, 4.66; N, 8.82.

EXAMPLE 15 3-(4-Aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

3-(4-Aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was preparedanalogously to 3-(3,4-dimethoxyphenyl)-3-(3-aminophenyl)acrylonitrileusing 3-(3,4-dimethoxyphenyl) 3-(4-nitrophenyl)acrylonitrile (1.24 g, 4mmol) and 0.15 g of 10% palladium on carbon catalyst in 100 mL of ethylacetate. The crude mixture was purified by flash column chromatography(silica gel, 5% ethyl acetate/methylene chloride) to afford 0.19 g (17%)of a mixture of the E and Z isomers as a yellow solid: mp 150–152° C.;¹H NMR (CDCl₃) δ 7.38–6.56 (m, 14H); 5.51 (s, 1H), 5.44 (s, 1H), 3.97(br s, 4H), 3.93 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H); ¹³ CNMR (CDCl₃) δ 162.8, 162.6, 150.8, 150.3, 148.8, 148.7, 148.5, 148.4,132.4, 131.4, 130.1, 129.5, 129.9, 128.6, 126.7, 123.0, 122.1, 114.4,114.3, 112.8, 111.6, 110.7, 90.3, 89.9, 56.0, 55.9; Anal. Calcd forC₁₇H₁₆N₂O₃. Theoretical: C, 72.84, H, 5.75; N, 9.99. Found: C, 72.79; H,5.83; N, 9.59.

EXAMPLE 16 3,4-Dimethoxy-4′-aminobenzophenone

3,4-Dimethoxy-4′-aminobenzophenone was prepared analogously to3,4-dimethoxy-3′-aminobenzophenone using3,4-dimethoxy-4′-nitrobenzophenone (1 g, 3.5 mmol) and 0.1 g of 10%palladium on carbon catalyst in 110 mL of ethyl acetate. The crudeproduct was purified by flash column chromatography (silica gel, 12%ethyl acetate/methylene chloride) to afford 0.32 g (36%) of the productas a yellow solid: mp 189–191° C.; ¹H NMR (CDCl₃) δ 7.80–7.62 (m, 2H);7.45–7.29 (m, 2H), 6.96–6.80 (m, 1H), 6.75–6.61 (m, 2H), 4.14 (s, 2H),3.95 (s, 3H), 3.93 (s, 3H); ¹³C NMR (CDCl₃) δ 194.2, 152.2, 150.5,148.8, 132.6, 131.3, 128.0, 124.3, 113.6, 112.3, 109.7, 56.0; Anal.Calcd for C₁₅H₁₅NO₃. Theoretical: C, 70.02; H, 5.88; N, 5.44. Found: C,69.95; H, 6.18; N, 5.13.

EXAMPLE 17 3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile

A. 3,4-Dimethoxy-4′-methylbenzophenone

The title compound was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (3.9 mL, 28 mmol),aluminum chloride (4.1 g, 31 mmol) and 4-methylbenzoyl chloride (4.6 mL,29 mmol) with a reaction time of 6 hours at room temperature. The crudemixture was purified by flash column chromatography (silica gel, 2%ethyl acetate/methylene chloride) to afford 4.22 g (59%) of the productas a white solid: mp 121.5–122° C.; ¹H NMR (CDCl₃) δ 7.70–7.67 (d, J=8Hz, 2H), 7.48–7.26 (m, 4H), 6.91–6.88 (d, J=8.3 Hz, 1H), 6.96 (s, 3H),3.94 (s, 3H), 2.44 (s, 3H); ¹³C NMR (CDCl₃) δ 195.1, 152.6, 148.8,142.4, 135.3, 130.3, 129.8, 128.7, 125.0, 112.0, 109.6, 55.9, 55.8,21.4; Anal. Calcd for C₁₆H₁₆O₃. Theoretical: C, 74.98; H, 6.29. Found:C, 74.84; H, 6.43.

B. 3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile

3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile was preparedanalogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using3,4-dimethoxy-4′-methylbenzophenone (2.3 g, 9 mmol),diethylcyanomethylphosphonate (1.8 mL, 9.9 mmol) and lithiumhexamethyldisilazide (10 mL, 9.9 mmol, 1M) with a reaction time of 22hours at room temperature. The crude product was purified bychromatography (silica gel, 1% ethyl acetate/methylene chloride) toafford 1.83 g (73%) of a mixture of the E and Z isomers as a whitesolid: mp 83.5–86.5° C.; ¹H NMR (CDCl₃) δ 7.35–7.20 (m, 8H), 7.04–6.81(m, 6H), 5.62 (s, 1H), 5.59 (s, 1H), 3.90 (s, 3H), 3.90 (s, 3H), 3.88(s, 3H), 3.82 (s, 3H), 2.41 (s, 3H), 2.39 (s, 3H); ¹³C NMR (CDCl₃) δ162.7, 162.6, 160.0, 150.4, 148.8, 148.5, 140.6, 140.1, 136.3, 134.1,131.6, 129.5, 129.2, 129.0, 128.5, 123.0, 122.1, 118.4, 118.3, 112.6,111.1, 110.7, 92.6, 92.4, 55.9, 55.9, 55.8, 21.3, 21.2; Anal. Calcd forC₁₈H₁₇NO₂. Theoretical: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.64; H,5.93; N, 5.01.

EXAMPLE 18 3-(4-Biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

A. 3,4-Dimethoxy-4′-phenylbenzophenone

3,4-Dimethoxy-4′-phenylbenzophenone was prepared analogously to3,4,3′,4′-tetra-methoxybenzophenone using veratrole (2.4 g, 17 mmol),aluminum chloride (2.5 g, 19 mmol) and 4-biphenylcarbonyl chloride (4 g,18 mmol) with a reaction time of 24 hours at room temperature. The crudeproduct was purified by flash column chromatography (silica gel, 2%ethyl acetate/methylene chloride) to afford 3.86 g (70%) of the productas a white solid: mp 103–104° C.; ¹H NMR (CDCl₃) δ 7.88–7.84 (m, 2H),7.73–7.64 (m, 4H), 7.52–7.40 (m, 5H), 6.93–6.90 (m, 1H), 3.97 (s, 3H),3.96 (s, 3H); ¹³C NMR (CDCl₃) δ 194.9, 152.9, 148.9, 144.5, 139.8,136.8, 130.2, 130.2, 128.8, 127.9, 127.1, 126.7, 125.2, 112.0, 109.7,55.9, 55.9; Anal. Calcd for C₂₁H₁₈O₃. Theoretical: C, 79.23; H, 5.70.Found: C, 78.91; H, 5.87.

B. 3-(4-Biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

3-(4-Biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was preparedanalogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using3,4-dimethoxy-4′-phenylbenzophenone (2.33 g, 7.32 mmol),diethylcyanomethylphosphonate (1.5 mL, 8.1 mmol) and lithiumhexamethyldisilazide (8.1 mL, 8.1 mmol, 1M) with a reaction time of 22hours. The crude product was purified by chromatography (silica gel, 1%ethyl acetate/methylene chloride) to afford 1.76 g (70%) of a mixture ofthe E and Z isomers as a white solid: mp 132.0–134° C.; ¹H NMR (CDCl₃) δ7.70–7.39 (m, 18H), 7.10–6.80 (m, 6H), 5.69 (s, 1H), 5.68 (s, 1H), 3.95(s, 6H), 3.93 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H); ¹³C NMR (CDCl₃) δ162.2, 151.1, 148.8, 148.6, 143.0, 142.6, 140.0, 137.9, 135.9, 131.4,130.1, 129.3, 129.1, 128.8, 128.8, 127.9, 127.1, 127.0, 126.0, 126.9,123.1, 122.2, 118.3, 118.2, 112.6, 111.1, 110.7, 93.2, 92.9, 56.0, 55.9,55.8; Anal. Calcd for C₂₃H₁₉NO₂. Theoretical: C, 80.92; H, 5.61; N,4.10. Found: C, 80.55; H, 5.80; N, 3.95.

EXAMPLE 19 3-(3,4-Dimethoxyphenyl)-3-(4′-fluorophenyl)acrylonitrile

3-(3,4-Dimethoxyphenyl)-3-(4′-fluorophenyl)acrylonitrile was preparedanalogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using3,4-dimethoxy-4′-fluorobenzophenone (1.3 g, 5 mmol),diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithiumhexamethyldisilazide (5.5 mL, 5.5 mmol, 1M) with a reaction time of 22hours at room temperature. The crude product was purified bychromatography (silica gel, 1% ethyl acetate/methylene chloride) toafford 2.38 g (55%) of a mixture of the E and Z isomers as a whitesolid: mp 100–102° C.; ¹H NMR (CDCl₃) δ 7.54–6.74 (m, 14H), 5.67 (s,1H), 5.57 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.83 (s,3H); ^(13 C NMR (CDCl) ₃) δ 166.0, 165.6, 162.0, 161.6, 151.3, 150.7,148.9, 148.7, 135.4, 135.4, 133.2, 133.1, 131.7, 131.6, 131.3, 130.7,130.5, 129.2, 123.1, 122.1, 118.1, 118.0, 115.8, 115.8, 115.5, 115.4,112.6, 111.0, 110.8, 93.4, 93.2, 56.0, 56.0, 55.9; Anal. Calcd forC₁₇H₁₄FNO₂. Theoretical: C, 72.07; H, 4.98; N, 4.94. Found: C, 71.91; H,4.98; N, 4.79.

EXAMPLE 20 3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylonitrile (E and ZIsomers)

A. 2-(3,4-Dimethoxybenzoyl)naphthalene

2-(3,4-Dimethoxybenzoyl)naphthalene was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (2.6 mL, 20 mmol),aluminum chloride (2.9 g, 22 mmol) and 2-naphthoyl chloride (3.9 g, 20mmol) with a reaction time of 4 hours at reflux. The crude product waspurified by flash column chromatography (silica gel, 2.5% ethylacetate/methylene chloride) to afford 4.52 g (77%) of the product as awhite solid: mp 120–121.5° C.; ¹H NMR (CDCl₃) δ 8.24 (s, 1H), 8.03–7.84(m, 4H), 7.68–7.40 (m, 4H), 7.00–6.87 (m, 1H), 3.97 (s, 3H), 3.95 (s,3H); ¹³C NMR (CDCl₃) δ 195.5, 153.0 149.0, 135.5, 134.9, 132.2, 131.0,130.4, 129.2, 128.1, 128.0, 127.8, 126.7, 125.9, 125.4, 112.2, 109.8,56.1, 56.0; Anal. Calcd for C₁₉H₁₆O₃. Theoretical: C, 78.06; H, 5.52.Found: C, 77.73; H, 5.69.

B. 3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylonitrile

3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylontrile was preparedanalogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using2-(3,4-dimethoxybenzoyl)naphthalene (2.9 g, 10 mmol),diethylcyanomethylphosphonate (1.8 mL, 11 mmol) and lithiumhexamethyldisilazide (8.5 mL, 11 mmol 1.3M) with a reaction time of 1hour at reflux. The crude product was purified by chromatography (silicagel, methylene chloride) to afford 2.93 g (93%) of a mixture of the Eand Z isomers as a white solid: mp 121–123° C.; ¹H NMR (CDCl₃) δ8.11–6.78 (m, 20H), 5.76 (s, 1H), 5.75 (s, 1H), 3.96 (s, 3H), 3.92 (s,3H), 3.85 (s, 3H), 3.80 (s, 3H); ¹³C NMR (CDCl₃) δ 162.7, 162.7, 151.2,150.6, 148.9, 148.7, 136.6, 134.5, 134.0, 133.8, 132.8, 131.5, 129.7,129.4, 129.0, 128.6, 128.6, 128.3, 128.1, 127.7, 127.7, 127.4, 127.2,126.8, 126.6, 125.4, 123.2, 122.2, 118.4, 118.2, 112.7, 111.1, 110.8,93.9, 93.4, 56.0, 56.0, 55.9; Anal. Calcd for C₂₁H₁₇NO₂. Theoretical: C,79.98; H 5.43; N, 4.44. Found: C, 79.90; H, 5.65; N, 4.46.

EXAMPLE 213-(3,4-Dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile (E andZ Isomers)

A. 1-(3,4-Dimethoxybenzoyl)-3,4-methylenedioxybenzene

1-(3,4-Dimethoxybenzoyl)-3,4-methylenedioxybenzene was preparedanalogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3mL, 10 mmol), aluminum chloride (1.5 g, 11 mmol) and piperonyloylchloride (1.9 g, 10 mmol) with a reaction time of 2.5 hours at roomtemperature. The crude product was purified by flash columnchromatography (silica gel, 5% ethyl acetate/methylene chloride) toafford 1.99 g (69%) of the product as a white solid: mp 164–165° C.; ¹HNMR (CDCl₃) δ 7.46–7.26 (m, 4H), 6.95–6.82 (m, 2H), 6.06 (s, 2H), 3.96(s, 3H), 3.94 (s, 3H); ¹³C NMR (CDCl₃) δ193.9, 152.7, 151.0, 148.9,147.8, 132.4, 130.6, 126.1, 124.8, 112.2, 109.9, 109.7, 107.6, 101.7,56.0, 56.0; Anal. Calcd for C₁₆H₁₄O₅. Theoretical: C, 67.13; H, 4.93.Found: C, 66.86; H, 5.11.

B. 3-(3,4-Dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile

3-(3,4-Dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile wasprepared analogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylateusing 1-(3,4-dimethoxy-benzoyl)-3,4-methylenedioxybenzene (1.43 g, 5mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithiumhexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 1hour at reflux and 24 hours at room temperature. The crude product waspurified by chromatography (silica gel, 2% ethyl acetate/methylenechloride) to afford 0.79 g (51%) of a mixture of the E and Z isomers asan off white solid: mp 121–123° C.; ¹H NMR (CDCl₃) δ 7.10–6.73 (m, 12H),6.13–5.94 (m, 4H), 5.57 (s, 1H), 5.53 (s, 1H), 3.94 (s, 3H), 3.92 (s,3H), 3.87 (s, 3H), 3.84 (s, 3H); ¹³C NMR (CDCl₃) δ 162.3, 151.0, 150.5,149.6, 149.1, 148.8, 148.5, 147.9, 133.2, 131.6, 130.8, 129.4, 124.3,123.5, 123.1, 122.1, 118.5, 118.3, 112.6, 111.1, 110.7, 109.9, 108.5,108.2, 101.6, 101.5, 92.2, 92.2, 56.0, 55.9, 55.9; Anal. Calcd forC₁₈H₁₅NO₄. Theoretical C, 69.89; H, 4.89; N, 4.53. Found: C, 69.61; H,5.01; N, 4.37.

EXAMPLE 22 3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile (E and ZIsomers)

A. 4-(3,4-Dimethoxybenzoyl)pyridine

A hexane solution of butyl lithium (9 mL, 22 mmol, 2.5M) was slowlyadded to a stirring solution of 4-bromoveratrole (2.9 mL, 20 mmol) in 40mL of tetrahydrofuran under nitrogen at −70° C. After 15 minutes asolution of 4-cyanopyridine in 12 mL of tetrahydrofuran was added to thereaction mixture and stirring was continued for 45 minutes. The reactionwas then allowed to warm to −10° C. and the reaction was carefullyquenched with hydrochloric acid (45 mL, 1N). The mixture was stirred for30 minutes at room temperature. The pH was then adjusted to 12 with 50mL of a 10% aqueous solution of sodium hydroxide. The mixture wasextracted with ether (3×50 mL). The combined ethereal extracts werewashed with brine (100 mL) then dried over magnesium sulfate andconcentrated in vacuo to a brown solid. The crude product was purifiedby flash column chromatography (silica gel, 3% methanol/methylenechloride) to afford after vacuum drying (60° C., 1 mm) 1.9 g (39%) ofthe product: mp 117–118° C.; ¹H NMR (CDCl₃) δ 8.85–8.76 (m, 2H),7.60–7.50 (m, 3H), 7.40–7.30 (m, 1H), 6.97–6.88 (m, 1H), 3.98 (s, 3H),3.96 (s, 3H); ¹³C NMR (CDCl₃) δ 193.7, 153.9, 150.1, 149.3, 145.2,128.7, 125.9, 122.6, 111.5, 109.9, 56.1, 56.0; Anal. Calcd forC₁₄H₁₃NO₃. Theoretical: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.05; H,5.39; N, 5.85.

B. 3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile

3-(3,4-Dimethoxyphenyl)-3-pyridin-4-ylacrylonitrile was preparedanalogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using4-(3,4-dimethoxybenzoyl)pyridine (1 g, 4 mmol),diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithiumhexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 24hours at room temperature. The crude product was slurried in 10 mL ofhexane. The mixture was filtered, the solid was washed with hexane, airdried and then dried in vacuo to afford 0.91 g (85%) of a mixture of theE and Z isomers as an off white solid: mp 116–125° C.; ¹H NMR (CDCl₃) δ8.80–8.63 (m, 4H), 7.40–7.20 (n, 4H), 7.04–6.74 (m, 6H 5.81 (s, 1H),5.70 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H);¹³C NMR (CDCl₃) δ 160.1, 157.0, 151.6, 151.1, 150.3, 149.2, 148.9,146.7, 144.9, 129.6, 127.8, 123.7, 123.1, 122.7, 122.1, 117.4, 117.1,112.3, 111.0, 110.5, 96.1, 94.8, 56.0, 56.0; Anal. Calcd for C₁₆H₁₄N₂O₂.Theoretical: C, 72.17; H, 5.30; N, 16.52. Found: C, 72.35; H, 5.43; N,10.47.

EXAMPLE 23 3-(3,4-Dimethoxyphenyl)-3-pyridin-2-ylacrylonitrile

A. 2-(3,4-Dimethoxybenzoyl)pyridine

2-(3,4-Dimethoxybenzoyl)pyridine was prepared analogously to4-(3,4-dimethoxybenzoyl)pyridine using 2-cyanopyridine. The crudemixture was purified by flash column chromatography (silica gel, 1%methanol/methylene chloride) to afford after drying in vacuo (60° C., 1mm) 1.67 g (34%) of the product: mp 91.5–93° C.; ¹H NMR (CDCl₃) δ8.76–8.70 (m, 1H), 8.05–7.71 (m, 4H), 7.55–7.45 (m, 1H), 7.00–6.89 (m,1H), 3.96 (s, 3H), 3.96 (s, 3H); ¹³C NMR (CDCl₃) δ 192.1, 155.7, 153.3,148.7, 148.2, 136.9, 128.9, 126.7, 125.7, 124.4, 112.6, 109.8, 56.0,55.9; Anal. Calcd for C₁₄H₁₃NO₃. Theoretical: C, 69.12; H, 5.39; N,5.76. Found: C, 68.96; H, 5.47; N, 5.66.

B. 3-(3,4-Dimethoxyphenyl)-3-pyridin-2-ylacrylonitrile

3-(3,4-Dimethoxyphenyl)-3-pyridin-2-yl)acrylonitrile was preparedanalogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using2-(3,4-dimethoxybenzoyl)pyridine (1 g, 4 mmol),diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithiumhexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 17hours at room temperature. The crude product was purified by flashcolumn chromatography (silica gel, 1% methanol/methylene chloride) toafford 0.8 g (75%) of a mixture of the E and Z isomers as a brown solid.The isomers were separated by additional purification (silica gel, 10%ethyl acetate/methylene chloride) to afford pure samples of each of theisomers.

Isomer 1: mp 125–126° C.; ¹H NMR (CDCl₃) δ 8.75–8.65 (m, 1H), 7.75–7.60(m, 1H), 7.41–7.16 (m, 2H), 7.10–6.90 (m, 3H), 6.52 (s, 1H), 3.95 (s,3H), 3.89 (s, 3H); ¹³C NMR (CDCl₃) δ 159.9, 154.9, 150.4, 149.9, 148.9,136.7, 128.0, 124.6, 124.1, 122.6, 118.1, 112.4, 111.1, 97.8, 56.1,56.0; Anal. Calcd for C₁₆H₁₄N₂O₂. Theoretical: C, 72.17; H, 5.30; N,10.52. Found: C, 71.90; H, 5.28; N, 10.33.

Isomer 2: mp 134.5–135.5° C.; ¹H NMR (CDCl₃) δ 8.82–8.70 (m, 1H),7.88–7.76 (m, 1H), 7.60–7.34 (m, 2H), 6.94–6.80 (m, 3H), 5.82 (s, 1H),3.91 (s, 3H), 3.83 (s, 3H); ¹³C NMR (CDCl₃) δ 160.8, 155.3, 151.2,149.9, 149.0, 136.6, 130.2, 124.9, 124.3, 122.1, 117.6, 110.9, 95.4,56.0; Anal. Calcd for C₁₆H₁₄N₂O₂. Theoretical: C, 72.17; H, 5.30; N,10.52. Found: C, 72.13; H, 5.23; N, 10.40.

EXAMPLE 24 3-(3,4-Dimethoxyphenyl)-3-(2-furyl)acrylonitrile (E and ZIsomers)

A. 2-(3,4-Dimethoxybenzoyl)furane

2-(3,4-Dimethoxybenzoyl)furane was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol),aluminum chloride (1.5 g, 10 mmol) and 2-furoyl chloride (1.1 mL, 10mmol) with a reaction time of 2 hours at reflux. The crude product waspurified by flash column chromatography (silica gel, 4% ethylacetate/methylene chloride) to afford 1.69 g (78%) of the product as awhite solid: mp 112–114° C.; ¹H NMR (CDCl₃) δ 7.78–7.66 (m, 2H),7.59–7.52 (m, 1H), 7.26–7.17 (m, 1H), 6.96–6.90(m, 1H), 6.63–6.55 (m,1H), 3.97 (s, 3H), 3.96 (s, 3H); ¹³C NMR (CDCl₃) δ 180.9, 153.0, 152.5,148.9, 146.5, 129.8, 124.0, 119.6, 112.0, 111.7, 110.0, 56.0, 55.9;Anal. Calcd for C₁₃H₁₂O₄. Theoretical: C, 67.23; H, 5.21. Found: C,67.09; H, 5.21.

B. 3-(3,4-Dimethoxyphenyl)-3-(2-furyl)acrylonitrile

3-(3,4-Dimethoxyphenyl)-3-(2-furyl)acrylonitrile was preparedanalogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using2-(3,4-dimethoxybenzoyl)furane (0.87 g, 4 mmol),diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithiumhexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 3hours at room temperature. The crude product was purified bychromatography (silica gel, 2% ethyl acetate/methylene chloride) toafford 0.78 g (76%) of a mixture of the E and Z isomers as an off whitesolid: mp 78–82° C.; ¹H NMR (CDCl₃) δ 7.68–7.73 (m, 2H), 7.16–6.75 (m,7H), 6.54–6.39 (m, 3H), 5.87 (s, 1H), 5.30 (s, 1H), 3.93 (s, 3H), 3.93(s, 3H), 3.91 (s, 3H), 3.88 (s, 3H); ¹³C NMR (CDCl₃) δ 152.0, 150.7,150.5, 150.4, 149.3, 148.8, 148.7, 148.7, 145.2, 145.0, 129.6, 126.7,122.1, 121.6, 118.1, 118.0, 116.5, 115.6, 112.5, 112.1, 112.0, 111.5,110.9, 110.8, 90.5, 90.2, 55.9, 55.9, 55.9, 55.8; Anal. Calcd forC₁₅H₁₃NO₃. Theoretical: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.61; H,5.09; N, 5.18.

EXAMPLE 25 3-(3,4-Diethylphenyl)-3-phenylacrylonitrile (E and Z Isomers)

A. 3,4-Diethylbenzophenone

To a stirred ice bath cooled solution of diethylbenzene (1.7 mL, 10mmol) in methylene chloride (30 mL) under nitrogen was added aluminumchloride (2.93 g, 22 mmol). A slight exotherm resulted. To the resultingreaction mixture was added benzoyl chloride (1.2 mL, 10 mmol). Thereaction mixture was allowed to warm to room temperature and was thenstirred at room temperature for 1.5 hours. The reaction mixture waspoured into 60 mL of iced water and stirred for 20 minutes. Theresulting mixture was extracted with methylene chloride (2×40 mL). Thecombined extracts were dried over magnesium sulfate and concentrated invacuo to afford the crude product as an orange oil. The crude productwas purified by flash column chromatography (silica gel, 2.5% ethylacetate/hexane) to afford 1.22 g (51%) of the product as a yellow oil:¹H NMR (CDCl₃) δ 7.85–7.41 (m, 7H), 7.30–7.20 (m, 1H) 2.83–2.61 (m, 4H),1.35–1.17 (m, 6H); ¹³C NMR (CDCl₃) δ 196.8, 147.0, 141.9, 138.1, 135.3,132.1, 132.1, 130.1, 130.0, 128.1, 128.1, 25.6, 25.4, 15.1, 15.0; Anal.Calcd for C₁₇H₁₈O. Theoretical: C, 85.67; H, 7.61. Found: C, 85.38; H,7.42.

B. 3-(3,4-Diethylphenyl)-3-phenylacrylonitrile

3-(3,4-Diethylphenyl)-3-phenylacrylonitrile was prepared analogously tomethyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using3,4-diethylbenzophenone (0.95 g, 4 mmol), diethylcyanomethylphosphonate(0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol,1.3M) with a reaction time of 2 hours at room temperature. The crudeproduct was purified by flash chromatography (silica gel, 8% ethylacetate/methylene chloride) to afford an oil which was stirred in hexaneuntil it solidified. The resulting slurry was filtered, the solid washedwith hexane, air dried and then dried in vacuo to afford 0.6 g (57%) ofa mixture of the E and Z isomers as a white solid: mp 63–64° C.; ¹H NMR(CDCl₃) δ 7.51–6.99 (m, 16H), 5.72 (s, 2H), 2.76–2.55 (m, 8H), 1.32–1.14(m, 12H); ¹³C NMR (CDCl₃) δ 163.3, 144.7, 142.2, 137.3, 136.5, 130.2,129.8, 129.6, 128.6, 128.5, 128.4, 128.3, 127.2, 126.2, 118.2, 93.9,93.7, 25.5, 25.3, 15.2, 15.0.

EXAMPLE 26 3-(3,4-Diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

A. 3′,4′-Diethyl-3,4-dimethoxybenzophenone

3′,4′-Diethyl-3,4-dimethoxybenzophenone was prepared analogously to3,4-diethylbenzophenone using diethylbenzene (2.5 mL, 15 mmol), aluminumchloride (2.2 g, 16.5 mmol) and 3,4-dimethoxybenzoyl chloride (3 g, 15mmol) with a reaction time of 3 hours at reflux. The crude product waspurified by flash column chromatography (silica gel, 1.5% ethylacetate/hexane) to afford 0.84 g (20%) of the product as an orangesolid: mp 60–61° C.; ¹H NMR (CDCl₃) δ 7.74–7.15 (m, 5H), 7.00–6.80 (m,1H) 3.96 (s, 3H) 3.94 (s, 3H), 2.93–2.60 (m, 4H), 1.43–1.15 (m, 6H); ¹³CNMR (CDCl₃) δ 195.5, 152.7, 148.8, 146.3, 141.7, 135.9, 130.6, 129.8,128.0, 127.7, 125.1, 112.2, 109.7, 56.0, 25.6, 25.4, 15.1, 15.0; Anal.Calcd for C₁₉H₂₂O₃. Theoretical: C, 76.48; H, 7.43. Found: C, 76.53; H,7.34.

B. 3-(3,4-Diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile

3-(3,4-Diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was preparedanalogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using3′,4′-diethyl-3,4-dimethoxybenzophenone (0.51 g, 1.7 mmol),diethylcyanomethylphosphonate (0.31 mL, 1.9 mmol) and lithiumhexamethyldisilazide (1.4 mL, 1.9 mmol, 1.3M) with a reaction time of 60hours at room temperature. The crude product was purified bychromatography (silica gel, 1% ethyl acetate/methylene chloride) toafford an oil which was stirred in hexane until it solidified. Theresulting slurry was filtered, the solid washed with hexane, air dried,and dried in vacuo to afford 0.31 g (57%) of a mixture of the E and Zisomers as an off white solid: mp 78–82° C.; ¹H NMR (CDCl₃) δ 7.30–6.75(m, 12H), 5.61 (s, 1H), 5.60 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87(s, 3H), 3.83 (s, 3H), 2.80–2.59 (m, 8H), 1.35–1.14 (m, 12H); ¹³C NMR(CDCl₃) δ 163.0, 163.0, 151.0, 150.5, 148.8, 148.6, 144.6, 143.9, 142.1,141.8, 136.8, 134.5, 131.9, 129.7, 128.6, 128.5, 128.2, 127.3, 126.3,123.2, 122.2, 118.7, 118.6, 112.8, 111.3, 110.7, 92.5, 92.2, 56.1, 56.0,25.5, 25.4, 25.4, 25.3, 15.3, 15.2, 15.0, 14.9; Anal. Calcd forC₂₁H₂₃NO₂. Theoretical: C, 78.47; H, 7.21; N, 4.36. Found: C, 77.80; H,7.25; N, 4.68.

EXAMPLE 27 4-(3-Ethoxy-4-methoxyphenyl)-4-phenyl-3-butan-2-one

To a suspension of cuprous cyanide (0.21 g, 2.3 mmol) in tetrahydrofuran(8 mL) at −70° C. under nitrogen was added a cyclohexyl/ether solutionof phenyl lithium (2.6 mL, 4.6 mmol, 1.8M). After 45 minutes a solutionof 4-(3-ethoxy-4-methoxyphenyl)-3-buten-2-one (0.51 g, 2,3 mmol) in 10mL of tetrahydrofuran was slowly added to the reaction mixture. After 1hour at −78° C. the mixture was allowed to warm to room temperature. Thereaction mixture was then carefully quenched with 10 mL of an aqueoussolution of ammonium chloride. The resulting mixture was extracted withmethylene chloride (3×10 mL). The combined organic extracts were driedover magnesium sulfate and concentrated in vacuo to afford 0.7 g of thecrude product. The crude product was purified by chromatography (silicagel, 2% ethyl acetate/methylene chloride) to afford 0.41 g (60%) of theproduct as an oil which solidified: mp 57–58° C.; ¹H NMR (CDCl₃) δ7.31–7.13 (m, 5H), 6.83–6.69 (m, 3H), 4.48 (t, J=7.5 Hz, 1H), 4.03 (q,J=7 Hz, 2H), 3.82 (s, 3H), 3.13 (d, J=7.5 Hz, 2H), 2.07 (s, 3H), 1.41(t, J=7 Hz, 3H); ¹³C NMR (CDCl₃) δ 207.0, 148.2, 148.0, 144.2, 136.4,128.6, 127.6, 126.4, 119.4, 113.0, 111.5, 64.3, 55.9, 49.9, 45.6, 30.6,14.8; Anal. Calcd for C₁₉H₂₂O₃. Theoretical: C, 76.48; H, 7.43. Found:C, 76.81; H, 7.44.

EXAMPLE 28 3-(3,4-Dimethoxyphenyl)-3-(naphth-1-yl)acrylonitrile

1-(3,4-Dimethoxybenzoyl)naphthalene was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol),aluminum chloride (11.5 g, 11 mmol) and 1-naphthoyl chloride (1.5 mL, 10mmol) with a reaction time of 24 hours at room temperature. The crudeproduct was purified by flash column chromatography (silica gel, 2.5%ethyl acetate/methylene chloride) to afford 1.85 g (63%) of the productas a white solid: mp 92.5–94.5° C.; ¹H NMR (CDCl₃) δ 8.06–7.84 (m, 3H),7.80–7.39 (m, 5H), 7.31–7.21 (m, 1H), 6.84–6.74 (m, 1H), 3.94 (s, 3H),3.91 (s, 3H); ¹³C NMR (CDCl₃) δ 196.6, 153.5, 149.0, 136.8, 133.6,131.1, 130.9, 130.5, 128.2, 126.9, 126.7, 126.3, 126.3, 125.6, 124.3,111.3, 109.7, 56.0, 55.9; Anal. Calcd for C₁₉H₁₆O₃. Theoretical: C,78.06; H, 5.52. Found: C, 77.97; H, 5.66.

3-(3,4-Dimethoxyphenyl)-3-(naphth-1-yl)acrylonitrile is prepared in afashion similar to that described in Example 20.

EXAMPLE 29 3-(3,4-Dimethoxyphenyl)-3-(2,5-dichlorophenyl)acrylonitrile

2′,5′-Dichloro-3,4-dimethoxybenzophenone was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone using veratrole (2.15 mL, 15 mmol),aluminum chloride (2.2 g, 16.5 mmol) and 2,5-dichlorobenzoyl chloride(1.9 mL, 15 mmol) with a reaction time of 3 hours at reflux. The crudeproduct was purified by flash column chromatography (silica gel, 2.5%ethyl acetate/methylene chloride) to afford 3.88 g (83%) of the productas a white solid: mp 129–130° C.; ¹H NMR (CDCl₃) δ 7.65–7.56 (m, 1H),7.41–7.12 (m, 4H), 6.89–6.81 (m, 1H), 3.96 (s, 3H), 3.94 (s, 3H); ¹³CNMR (CDCl₃) δ 191.1, 154.4, 149.6, 137.9, 132.0, 130.5, 128.7, 128.0,125.7, 110.2, 56.1, 56.0; Anal. Calcd for C₁₅H₁₂Cl₂O₃. Theoretical: C,57.90; H, 3.89. Found: C, 57.58; H, 3.87.

3-(3,4-Dimethoxyphenyl)-3-(2,5-dichlorophenyl)acrylonitrile is preparedin an analogous fashion as described in Example 26 starting with5′-dichloro-3,4-dimethoxybenzophenone.

EXAMPLE 30 2′,6′,3,4-Tetramethoxybenzophenone

2′,6′,3,4-Tetramethoxybenzophenone was prepared analogously to3,4,3′,4′-tetramethoxybenzophenone except using veratrole (1.3 mL, 10mmol), aluminum chloride (1.47 g, 11 mmol) and 2,6-dimethoxybenzoylchloride (2.0 mL, 10 mmol) with a reaction time of 24 hours at roomtemperature. The crude mixture was purified by flash columnchromatography (silica gel, 4% ethyl acetate/methylene chloride) toafford 2.11 g (70%) of the product as a white solid: mp 128–129° C.; ¹HNMR (CDCl₃) δ 7.66–7.60 (m, 1H), 7.40–7.20 (m, 2H), 6.88–6.79 (m, 1H),6.67–6.65 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.71 (s, 6H); ¹³C NMR(CDCl₃) δ 193.8, 157.4, 153.4, 148.9, 130.9, 130.5, 125.3, 118.0, 110.2,109.9, 104.0, 55.9, 55.8; Anal. Calcd for C₁₇H₁₈O₅. Theoretical: C,67.54; H, 6.00. Found: C, 66.51; H, 5.91.

3-(3,4-Dimethoxyphenyl)-3-(2,6-dimethoxyphenyl)acrylonitrile is preparedin an analogous fashion as described in Example 10 starting with2′,6′,3,4-tetramethoxybenzophenone.

EXAMPLE 31

Tablets, each containing 50 milligrams of active ingredient, can beprepared in the following manner:

Constituents (for 1000 tablets) active ingredient 50.0 grams lactose50.7 grams wheat starch  7.5 grams polyethylene glycol 6000  5.0 gramstalc  5.0 grams magnesium stearate  1.8 grams demineralized water q.s.

The solid ingredients are first forced through a sieve of 0.6 mm meshwidth. The active ingredient, the lactose, the talc, the magnesiumstearate and half of the starch then are mixed. The other half of thestarch is suspended in 40 milliliters of water and this suspension isadded to a boiling solution of the polyethylene glycol in 100milliliters of water. The resulting paste is added to the pulverulentsubstances and the mixture is granulated, if necessary with the additionof water. The granulate is dried overnight at 35° C., forced through asieve of 1.2 mm mesh width and compressed to form tablets ofapproximately 6 mm diameter which are concave on both sides.

EXAMPLE 32

Tablets, each containing 100 milligrams of active ingredient, can beprepared in the following manner:

Constituents (for 1000 tablets) active ingredient 100.0 grams lactose100.0 grams wheat starch  47.0 grams magnesium stearate  3.0 grams

All the solid ingredients are first forced through a sieve of 0.6 mmmesh width. The active ingredient, the lactose, the magnesium stearateand half of the starch then are mixed. The other half of the starch issuspended in 40 milliliters of water and this suspension is added to 100milliliters of boiling water. The resulting paste is added to thepulverulent substances and the mixture is granulated, if necessary withthe addition of water. The granulate is dried overnight at 35° C.,forced through a sieve of 1.2 mm mesh width and compressed to formtablets of approximately 6 mm diameter which are concave on both sides.

EXAMPLE 33

Tablets for chewing, each containing 75 milligrams of active ingredient,can be prepared in the following manner:

Composition (for 1000 tablets) active ingredient  75.0 grams mannitol230.0 grams lactose 150.0 grams talc  21.0 grams glycine  12.5 gramsstearic acid  10.0 grams saccharin  1.5 grams 5% gelatin solution q.s.

All the solid ingredients are first forced through a sieve of 0.25 mmmesh width. The mannitol and the lactose are mixed, granulated with theaddition of gelatin solution, forced through a sieve of 2 mm mesh width,dried at 50° C. and again forced through a sieve of 1.7 mm mesh width.The active ingredient, the glycine and the saccharin are carefullymixed, the mannitol, the lactose granulate, the stearic acid and thetalc are added and the whole is mixed thoroughly and compressed to formtablets of approximately 10 mm diameter which are concave on both sidesand have a breaking groove on the upper side.

EXAMPLE 34

Tablets, each containing 10 milligrams of active ingredient, can beprepared in the following manner:

Composition (for 1000 tablets) active ingredient  10.0 grams lactose328.5 grams corn starch  17.5 grams polyethylene glycol 6000  5.0 gramstalc  25.0 grams magnesium stearate  4.0 grams demineralized water q.s.

The solid ingredients are first forced through a sieve of 0.6 mm meshwidth. Then the active ingredient, lactose, talc, magnesium stearate andhalf of the starch are intimately mixed. The other half of the starch issuspended in 65 milliliters of water and this suspension is added to aboiling solution of the polyethylene glycol in 260 milliliters of water.The resulting paste is added to the pulverulent substances, and thewhole is mixed and granulated, if necessary with the addition of water.The granulate is dried overnight at 35° C., forced through a sieve of1.2 mm mesh width and compressed to form tablets of approximately 10 mmdiameter which are concave on both sides and have a breaking notch onthe upper side.

EXAMPLE 35

Gelatin dry-filled capsules, each containing 100 milligrams of activeingredient, can be prepared in the following manner:

Composition (for 1000 capsules) active ingredient 100.0 gramsmicrocrystalline cellulose  30.0 grams sodium lauryl sulphate  2.0 gramsmagnesium stearate  8.0 grams

The sodium lauryl sulphate is sieved into the active ingredient througha sieve of 0.2 mm mesh width and the two components are intimately mixedfor 10 minutes. The microcrystalline cellulose is then added through asieve of 0.9 mm mesh width and the whole is again intimately mixed for10 minutes. Finally, the magnesium stearate is added through a sieve of0.8 mm width and, after mixing for a further 3 minutes, the mixture isintroduced in portions of 140 milligrams each into size 0 (elongated)gelatin dry-fill capsules.

EXAMPLE 36

A 0.2% injection or infusion solution can be prepared, for example, inthe following manner:

active ingredient  5.0 grams sodium chloride  22.5 grams phosphatebuffer pH 7.4 300.0 grams demineralized water to 2500.0 milliliters

The active ingredient is dissolved in 1000 milliliters of water andfiltered through a microfilter or slurried in 1000 mL of H₂O. The buffersolution is added and the whole is made up to 2500 milliliters withwater. To prepare dosage unit forms, portions of 1.0 or 2.5 milliliterseach are introduced into glass ampoules (each containing respectively2.0 or 5.0 milligrams of active ingredient).

1. A substantially pure (E)-compound, a substantially pure (Z)-compound,or a mixture of (E)- and (Z)-compounds having the formula (I):

wherein: X is —O—, and R¹ is any alkyl of up to 10 carbon atoms, anymonocycloalkyl of up to 10 carbon atoms, any polycycloalkyl of up to 10carbon atoms, or any benzocyclic alkyl of up to 10 carbon atoms; R² isnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, loweralkoxy, or halo; and R³ is (i) phenyl unsubstituted or substituted with1 or more substituents wherein each substituent is independently anitro, a cyano, a halo, a trifluoromethyl, a carbethoxy, a carbomethoxy,a carbopropoxy, an acetyl, a carbamoyl, a carbamoyl substituted with analkyl of 1 to 3 carbon atoms, an acetoxy, a carboxy, a hydroxy, anamino, an amino substituted with an alkyl of 1 to 5 carbon atoms, analkyl or cycloalkyl of 1 to 10 carbon atoms, or an alkoxy or cycloalkoxyof 1 to 10 carbon atoms; or (ii) phenyl substituted with 1 or moresubstituents wherein each substituent is independently analkylidenemethyl of up to 10 carbon atoms, a cycloalkylidenemethyl of upto 10 carbon atoms, a phenyl, or a methylenedioxy.
 2. The compound ormixture of claim 1, wherein: R² is nitro, cyano, trifluoromethyl, amino,lower alkyl, lower alkoxy, or halo.
 3. The compound or mixture of claim1, wherein: R¹ is alkyl of up to 10 carbon atoms; and R² istrifluoromethyl; lower alkyl, or lower alkoxy.
 4. The compound of claim3, wherein: R¹ is methyl or ethyl; and R² is methoxy or ethoxy.
 5. Asubstantially pure (E)-compound, a substantially pure (Z)-compound, or amixture of (E)- and (Z)-compounds having the formula (II):


6. The compound or mixture of claim 1 which is:3,3-bis-(3,4-dimethoxyphenyl)acrylonitrile;3,3-bis-(3-ethoxy-4-methoxyphenyl)acrylonitrile;3-(3-propoxy-4-methoxyphenyl)-3-phenylacrylonitrile;3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile;3,3-bis-(3-cyclopentoxy-4-methoxyphenyl)acrylonitrile;3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylacrylonitrile;3-(3,4-dimethoxyphenyl)-3-phenylacrylonitrile;3-(3,4-dimethoxyphenyl)-3-(3′,5′-dimethoxyphenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile;3-(3′-aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-(4-nitrophenyl)acrylonitrile;3-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile;3-(4-biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-(4′-fluorophenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile;3-(3,4-diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile; or3-(3,4-dimethoxyphenyl)-3-(2,5-dichlorophenyl)acrylonitrile.
 7. Apharmaceutical composition comprising a compound or mixture according toclaim
 1. 8. A compound of claim 1, which is an (E)-compound.
 9. Acompound of claim 1, which is an (Z)-compound.
 10. A mixture of claim 1comprising both (E)- and (Z)-compounds.
 11. A pharmaceutical compositioncomprising a compound or mixture according to claim
 3. 12. A compound ofclaim 3, which is an (E)-compound.
 13. A compound of claim 3, which isan (Z)-compound.
 14. A mixture of claim 3 comprising both (E)- and(Z)-compounds.
 15. A pharmaceutical composition comprising a compound ormixture according to claim
 5. 16. A compound of claim 5, which is an(E)-compound.
 17. A compound of claim 5, which is an (Z)-compound.
 18. Amixture of claim 5 comprising both (B)- and (Z)-compounds.